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CN118302413A - Anti-SARS-CoV-2 medicine - Google Patents

Anti-SARS-CoV-2 medicine Download PDF

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Publication number
CN118302413A
CN118302413A CN202280074839.2A CN202280074839A CN118302413A CN 118302413 A CN118302413 A CN 118302413A CN 202280074839 A CN202280074839 A CN 202280074839A CN 118302413 A CN118302413 A CN 118302413A
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mmol
added
compound
ymsa
solution
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Inventor
马场昌范
冈本实佳
外山政明
青木伸
田中智博
横井健汰
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Kagoshima University NUC
Tokyo University of Science
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Kagoshima University NUC
Tokyo University of Science
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及式(I)表示的化合物、其盐、它们的溶剂合物、或它们的前药、以及含有它们的抗SARS‑CoV‑2药。式(I)中，R1、R2及R3相同或不同，为氢原子、卤素原子、取代或未取代的C1‑6‑烷基、取代或未取代的C1‑6‑烷氧基、或者‑N(Ra)(Rb)(其中，Ra及Rb相同或不同，为取代或未取代的C1‑10‑烷基、或者取代或未取代的芳基，Ra及Rb可以与相邻的氮原子一起形成取代或未取代的5～7元环)，R4为‑N(Ra)(Rb)(其中，Ra及Rb相同或不同，为取代或未取代的C1‑10‑烷基、或者取代或未取代的芳基，Ra及Rb可以与相邻的氮原子一起形成取代或未取代的5～7元环)，X为氢原子、氟原子、氯原子、溴原子或碘原子，式中的羟基可以被保护基取代。 The present invention relates to compounds represented by formula (I), salts thereof, solvates thereof, or prodrugs thereof, and anti-SARS-CoV-2 drugs containing the same. In formula (I), R 1 , R 2 and R 3 are the same or different and are hydrogen atoms, halogen atoms, substituted or unsubstituted C 1-6 alkyl groups, substituted or unsubstituted C 1-6 alkoxy groups, or -N(R a )(R b ) (wherein, R a and R b are the same or different and are substituted or unsubstituted C 1-10 alkyl groups, or substituted or unsubstituted aryl groups, and R a and R b may form a substituted or unsubstituted 5- to 7-membered ring together with the adjacent nitrogen atom), R 4 is -N(R a )(R b ) (wherein, R a and R b are the same or different and are substituted or unsubstituted C 1-10 alkyl groups, or substituted or unsubstituted aryl groups, and R a and R b may form a substituted or unsubstituted 5- to 7-membered ring together with the adjacent nitrogen atom), X is hydrogen atoms, fluorine atoms, chlorine atoms, bromine atoms or iodine atoms, and the hydroxyl groups in the formula may be substituted with protecting groups.

Description

Anti-SARS-CoV-2 medicine
Technical Field
The present invention relates to anti-SARS-CoV-2 medicine.
Background
Coronaviruses are originally viruses responsible for the symptoms of the human cold, 4 coronaviruses are known, and 10 to 15% of the cold is caused by these viruses. In addition, coronaviruses causing Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) with high mortality are currently known. SARS patients were about 8,000, with a mortality rate of about 10%, MERS patients were about 2,500, and a mortality rate of about 35%.
Coronaviruses are positive strand RNA viruses with an envelope of about 100nm in diameter, SARS-CoV is classified as the second pathogen and MERS-CoV is classified as the third pathogen.
At present, adefovir, which has been diverted from various antibody drugs or anti-ebola drugs targeting spike proteins on the surface of SARS-CoV-2, is used as a therapeutic agent, and Mo Nupi-ravir developed as an anti-influenza drug or a newly developed combination package of nemaltavir tablet/ritonavir tablet (Paxlovid) is recognized as an orally administrable anti-SARS-CoV-2 drug. Mo Nupi the mechanism of action of ravir is believed to inhibit viral RNA-dependent RNA polymerase and to cause errors in viral RNA replication. In addition, the combination package of the nemaltevir tablet/ritonavir tablet is a mixture of a low molecular compound nemaltevir that inhibits the function of a main protease required for viral replication and ritonavir that functions as an accelerator for maintaining its blood concentration. However, these agents have some drawbacks such as malformation; there are problems in the use in combination with other agents; etc. Therefore, it is very important to identify and develop a novel agent having a selective and potent antiviral effect on SARS-CoV-2.
On the other hand, amodiaquine has been approved for clinical use as an antimalarial agent, and 7-chloro-4-aminoquinoline compounds such as amodiaquine are known to be effective for parkinson's disease (patent document 1). Furthermore, the present inventors have found that amodiaquine or a derivative thereof is effective against severe fever with thrombocytopenia syndrome virus (SFTSV) and ebola virus, and have filed patent applications (patent documents 2 and 3).
However, patent documents 1 to 3 do not teach the relationship between amodiaquine or a derivative thereof and anti-SARS-CoV-2 activity.
Prior art literature
Patent literature
Patent document 1: japanese patent application laid-open No. 2009-527478
Patent document 2: international publication No. 2018/135449
Patent document 3: international publication No. 2018/191642
Disclosure of Invention
Problems to be solved by the invention
The present invention aims to provide an antiviral agent effective against SARS-CoV-2.
Means for solving the problems
In order to solve the above problems, the present inventors established an anti-SARS-CoV-2 assay system for a pharmaceutical agent, and found that selective anti-SARS-CoV-2 effect was observed in amodiaquine and specific derivatives thereof by screening various pharmaceutical agents, and filed a patent application (PCT/JP 2021/18602).
As a result of further studies, the inventors of the present application have found that the quinoline skeleton of the compound described in PCT/JP2021/18602 is replaced with a quinazoline skeleton, whereby the toxicity is reduced while the antiviral activity is maintained, and have completed the present application.
Namely, the gist of the present invention is as follows.
(1) A compound represented by the following formula (I), a salt thereof, a solvate thereof, or a prodrug thereof,
[ Chemical formula 1]
[ R 1、R2 and R 3 are the same or different and are a hydrogen atom, a halogen atom, a substituted or unsubstituted C 1-6 -alkyl group, a substituted or unsubstituted C 1-6 -alkoxy group, or-N (R a)(Rb) (wherein R a and R b are the same or different and are a substituted or unsubstituted C 1-10 -alkyl group, or a substituted or unsubstituted aryl group, R a and R b may form a substituted or unsubstituted 5-to 7-membered ring together with the adjacent nitrogen atom),
R 4 is-N (R a)(Rb) (wherein R a and R b are the same or different and are a substituted or unsubstituted C 1-10 -alkyl group or a substituted or unsubstituted aryl group, R a and R b may form a substituted or unsubstituted 5-to 7-membered ring together with the adjacent nitrogen atom),
X is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom,
The hydroxyl group in the formula may be substituted with a protecting group. ].
(2) The compound according to the above (1), a salt thereof, a solvate thereof, or a prodrug thereof, wherein R 4 in the above formula (I) is ethyl (isopropyl) amino, diisopropylamino, cyclohexyl (ethyl) amino, ethyl (pentan-3-yl) amino, tert-butyl (ethyl) amino, or 3, 5-dimethylpiperidino.
(3) The compound according to the above (1) or (2), a salt thereof, a solvate thereof, or a prodrug thereof, wherein R 1、R2 and R 3 are the same or different and each is a hydrogen atom, a halogen atom, a C 1-6 -alkoxy group, or a dimethylamino group in the formula (I).
(4) The compound according to any one of (1) to (3), wherein X is a hydrogen atom or a chlorine atom, a salt thereof, a solvate thereof, or a prodrug thereof.
(5) An anti-SARS-CoV-2 agent comprising the compound according to any one of the above (1) to (4), a salt thereof, a solvate thereof, or a prodrug thereof.
(6) The use of the compound according to any one of the above (1) to (4), a salt thereof, a solvate thereof, or a prodrug thereof for producing an anti-SARS-CoV-2 drug.
ADVANTAGEOUS EFFECTS OF INVENTION
According to the present invention, an antiviral agent effective against SARS-CoV-2 can be provided.
Drawings
FIG. 1 shows a schematic representation of the anti-SARS-CoV-2 assay performed in the examples.
Detailed Description
The present invention will be described in detail below.
In the formula (I), the C 1-10 -alkyl group is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclopropylethyl, and the C 1-6 -alkyl group is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, cyclobutyl, cyclopentyl, cyclohexyl, and 2-cyclopropylethyl.
Examples of the C 1-6 -alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
The aforementioned C 1-10 -alkyl, C 1-6 -alkyl and C 1-6 -alkoxy groups may be substituted, for example, by one or more substituents selected from the group consisting of: c 1-6 -alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like; c 1-6 -alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl and cyclopentyloxycarbonyl; aromatic hydrocarbon groups such as phenyl, tolyl, and naphthyl; heterocyclyl groups such as pyridyl; halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; c 1-6 -aliphatic acyl groups such as formyl, acetyl, propionyl (propanoyl), butyryl (butanoyl), pentanoyl (pentanoyl), hexanoyl and the like; aromatic acyl (aroyl) such as benzoyl and toluoyl; aralkyloxy, carboxyl, hydroxyl, amino, C 1-6 -alkylamino, di-C 1-6 -alkylamino.
Examples of the aryl group include aromatic hydrocarbon groups such as phenyl and naphthyl, which may be substituted with one or more substituents selected from the group consisting of: c 1-6 -alkyl; c 1-6 -alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy; c 1-6 -alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl and cyclopentyloxycarbonyl; aromatic hydrocarbon groups such as phenyl, tolyl, and naphthyl; halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; c 1-6 -aliphatic acyl groups such as formyl, acetyl, propionyl (propanoyl), butyryl (butanoyl), pentanoyl (pentanoyl), hexanoyl and the like; aromatic acyl (aroyl) such as benzoyl and toluoyl; aralkyloxy, carboxyl, amino, C 1-6 -alkylamino, di C 1-6 -alkylamino.
Examples of the 5-to 7-membered cyclic group represented by R a and R b together with the adjacent nitrogen atom include a 1-pyrrolidinyl group, a 1-imidazolidinyl group, a 1-pyrazolidinyl group, a morpholino group (4-morpholino group), a piperidino group (1-piperidyl group), a 1-piperazinyl group, a 4-thiomorpholino group, a perhydro-1, 4-diazepin-1-yl group, a hexahydro-1H-azepin-1-yl group, a perhydro-1, 4-thiazepin-4-yl group, and these 5-to 7-membered cyclic groups may be substituted with 1 or more substituents selected from the group consisting of a C 1-6 -alkyl group, a C 2-6 -alkenyl group, a C 2-6 -alkynyl group, an aromatic group, an acyl group, a hydroxyl group, a carboxyl group, a cyano group, a halogen atom (for example, a fluorine atom), a C 1-6 -alkoxy group, an aralkyl group, a nitro group, an amino group, a C 1-6 -alkylamino group, a di-C 1-6 -alkylamino group, and the like. The 5-to 7-membered cyclic group is preferably a 5-membered cyclic group or a 6-membered cyclic group, and more preferably a substituted or unsubstituted 1-pyrrolidinyl group (e.g., 3-fluoro-1-pyrrolidinyl group), a substituted or unsubstituted 1-piperazinyl group (e.g., 4-methyl-1-piperazinyl group), a substituted or unsubstituted morpholino group (4-morpholinyl group), or a substituted or unsubstituted piperidino group (1-piperidyl group) (e.g., 3-fluoropiperidino group, 3, 5-dimethylpiperidino group).
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
The hydroxyl group in the above formula (I) may be substituted with a protecting group such as a 2-Tetrahydropyranyl (THP), 3,4, 5-trihydroxy-6-methyltetrahydropyran-2-yl group, methoxymethyl group, or the like.
From the viewpoint of the selection coefficient (50% toxic concentration (CC 50)/50% effective concentration (EC 50)), in the above formula (I), R 4 is preferably ethyl (isopropyl) amino, diisopropylamino, cyclohexyl (ethyl) amino, ethyl (pentan-3-yl) amino, tert-butyl (ethyl) amino or 3, 5-dimethylpiperidino, R 1、R2 and R 3 are the same or different and are a hydrogen atom, a halogen atom (preferably a fluorine atom), a C 1-6 -alkoxy group (preferably a methoxy group) or a dimethylamino group, and X is a hydrogen atom or a chlorine atom, and further preferably a combination thereof.
The compound of the present invention may have asymmetric carbon, and thus may have an optical isomer. In addition, the compounds of the present invention sometimes exist as tautomers. The compound of the present invention may be any of the isolated isomers (for example, R-isomer and S-isomer), or may be a mixture containing 2 or more isomers in any ratio, including racemates, diastereomers and the like.
The salt of the compound represented by the formula (I) is preferably a pharmaceutically acceptable salt, and examples thereof include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, nitric acid, pyrophosphoric acid, and metaphosphoric acid, or organic acids such as citric acid, benzoic acid, acetic acid, propionic acid, fumaric acid, maleic acid, and sulfonic acid (e.g., methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid).
Examples of the solvate of the compound represented by the formula (I) or a salt thereof include hydrates.
The compound represented by the aforementioned formula (I), a salt thereof, a solvate thereof, or a prodrug thereof may be a deuterium transformant that converts 1 H into 2 H (D). Such compounds are also included in the present invention.
In the present specification, "prodrug" means all compounds that, when administered to a biological system, produce a compound represented by formula (I) as a result of spontaneous chemical reaction or by catalyzing an enzyme or metabolic reaction. Preferably, the prodrug is a compound that is susceptible to administration into the body as a drug. Examples of the prodrug include pharmaceutically acceptable esters and amides. Specifically, examples of the group constituting the prodrug used in the hydroxyl group or the amino group include a C 2-7 -acyl group, a C 1-6 -alkoxy group (C 2-7 -acyl group), a C 1-6 -alkoxycarbonyl group (C 2-7 -acyl group), c 1-6 -alkoxycarbonyl, C 1-6 -alkoxy (C 2-7 -alkoxycarbonyl), (C 2-7 -acyloxy) methyl, 1- (C 2-7 -acyloxy) ethyl, (C 2-7 -alkoxycarbonyl) oxymethyl, 1- [ (C 2-7 -alkoxycarbonyl) oxy ] ethyl, etc., preferably C 2-7 -acyl, C 1-6 -alkoxycarbonyl. Examples of the group constituting the prodrug used in the carboxyl group include C 1-6 -alkyl, C 1-6 -alkoxy-C 1-6 -alkyl, (C 2-7 -acyloxy) methyl, 1- (C 2-7 -acyloxy) ethyl, (C 2-7 -alkoxycarbonyl) oxymethyl, 1- [ (C 2-7 -alkoxycarbonyl) oxy ] ethyl, etc., preferably C 1-6 -alkyl, C 1-6 -alkoxy-C 1-6 -alkyl.
The compound represented by the formula (I) can be produced, for example, as follows.
[ Chemical formula 2]
(Wherein the symbols have the same meaning as the above-mentioned (I))
That is, the target compound (I) can be produced by adding the 4-aminophenol derivative (A) to an ethanol solution of the 4-chloroquinazoline compound (B) and reacting the mixture under heating.
The compound in which R 1、R2 or R 3 in the compound (I) is a halogen atom, for example, a chlorine atom, can be converted into a compound in which R 1、R2 or R 3 in the formula (I) is-N (R a)(Rb) by reacting with NH (R a)(Rb)·HCl(Ra and R b have the same meaning as in the above (I)), for example, dimethylamine hydrochloride.
In order to purify the product obtained in the above manner, a generally used method, for example, column chromatography using silica gel or the like as a carrier, a recrystallization method using methanol, ethanol, chloroform, dimethyl sulfoxide, n-hexane-ethyl acetate, water or the like may be used. Examples of the eluting solvent for column chromatography include methanol, ethanol, chloroform, acetone, hexane, methylene chloride, ethyl acetate, and a mixed solvent thereof.
The aforementioned compounds can be formulated as anti-SARS-CoV-2 drugs in combination with conventional carriers for formulations. The administration form is not particularly limited, and may be appropriately selected and used as needed, and examples thereof include: oral preparations such as tablets, capsules, granules, fine granules, powders, sustained-release preparations, liquid preparations, suspensions, emulsions, syrups, elixirs and the like; parenteral formulations such as injections and suppositories.
The oral preparation can be produced by a conventional method using, for example, starch, lactose, white sugar, mannitol, carboxymethyl cellulose, inorganic salts, and the like. In addition, a binder, a disintegrant, a surfactant, a lubricant, a fluidity accelerator, a flavoring agent, a coloring agent, a perfume, and the like may be appropriately added in addition to these.
Examples of the binder include starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, and polyethylene glycol.
Examples of the disintegrating agent include starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.
Examples of the surfactant include sodium dodecyl sulfate, soybean lecithin, sucrose fatty acid ester, and polysorbate 80.
Examples of the lubricant include talc, waxes, hydrogenated vegetable oils, sucrose fatty acid esters, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol, and the like.
Examples of the fluidity accelerator include light silicic anhydride, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate, and the like.
The injection is prepared by a conventional method, and distilled water for injection, physiological saline, aqueous dextrose solution, olive oil, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like can be generally used as diluents. Optionally adding bactericide, antiseptic, stabilizer, isotonic agent, and relieving agent. From the viewpoint of stability, the injection may be filled into a vial or the like, frozen, and then the water removed by a usual freeze-drying technique, whereby a liquid preparation may be prepared from the freeze-dried product immediately before use. The proportion of the compound of formula (I) in the injection may vary from 5 to 50% by weight, but is not limited thereto.
As other parenteral agents, suppositories for intrarectal administration and the like, which are produced by a conventional method, can be mentioned.
The anti-SARS-CoV-2 formulated drug varies depending on the dosage form, administration route, etc., and can be administered, for example, 1 to 4 times per day over a period of 1 week to 3 months.
The anti-SARS-CoV-2 medicine of the invention is used for treating COVID-19. In the present invention, treatment also includes preventing severe cases.
In order to exert the desired effect, the weight of the compound of formula (I) is usually 0.1 to 1000mg, preferably 1 to 500mg, for example, in the case of an adult, and the weight of the compound is preferably taken in 1 day, depending on the age, weight, and extent of the disease of the patient.
In order to exert the desired effect, the compound of formula (I) is administered, for example, by intravenous injection, intravenous drip injection, subcutaneous injection or intramuscular injection, in an amount of 0.1 to 1000mg, preferably 1 to 500mg, as the weight of the compound of formula (I) in the case of an adult, depending on the age, weight and extent of the disease of the patient.
The compound represented by the above formula (I), a salt thereof, a solvate thereof, or a prodrug thereof may be contained in the pharmaceutical composition as the only active ingredient, or may contain other active ingredients.
The compound represented by the formula (I), a salt thereof, a solvate thereof, or a prodrug thereof may be used in combination with other agents effective for SARS-CoV-2 infection. They are administered separately during the course of treatment or in combination with a compound represented by the aforementioned formula (I) in a single dosage form such as a tablet, intravenous solution, or capsule. Examples of such other agents include adefovir.
Coronaviruses are known to infect in a variety of animals, and SARS-CoV is also known to cross the species wall and infect in a variety of animals. Thus, the subject of treatment with the anti-coronavirus agent of the present invention is not limited to humans, and includes various animals such as pets (e.g., dogs, cats), pigs, camels, bats, castors, tigers, mink mice, syrian hamsters, jades, sparks, and the like.
The present specification includes what is described in the specification and/or drawings of Japanese patent application No. 2021-18492, which is the basis of the priority of the present application.
Examples
The present invention will be described more specifically with reference to examples, but the scope of the present invention is not limited to these examples.
EXAMPLE 1 anti-SARS-CoV-2 Effect
A schematic representation of the anti-SARS-CoV-2 assay is shown in FIG. 1.
VeroE6/TMPRSS2 cells with high sensitivity to SARS-CoV-2 were seeded onto microplates (2X 10 4 cells/well). After 24 hours of incubation, various concentrations of the agent and SARS-CoV-2 (WK-521) (obtained from the national infection institute) were added at a multiplicity of infection (MOI) =0.01, followed by incubation at 37℃for 3 days. After the culture, 110. Mu.L of the culture supernatant was discarded, and 10. Mu.L of Cell Counting Kit-8 (from the same company as the Kernel chemical institute) was added (a kit for measuring the number of living cells using the water-soluble tetrazolium salt WST-8 (2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfophenyl) -2H-tetrazolium monosodium salt) as a chromogenic reagent). After 2 hours of incubation, 100. Mu.L of 2-propanol hydrochloride was added, and after thorough mixing, the absorbance of each well was measured at 450/620 nm. The anti-SARS-CoV 2 effect and cytotoxicity of the agent are determined by comparing the number of living cells in the infected cells and the uninfected cells, respectively, with the number of living cells without the agent.
The anti-SARS-CoV-2 effect of each quinazoline derivative is shown in tables 1 to 3.
TABLE 1
TABLE 2
TABLE 3
EC 50: 50% effective concentration (concentration of agent inhibiting 50% of cell death induced by SARS-CoV-2 infection)
CC 50: 50% toxicity concentration (concentration of agent to reduce viable cell count of uninfected cells by 50%)
The anti-SARS-CoV-2 effect of the compound in which the hydroxyl group at the 4-position of the 4-substituted phenylamino group of the quinazoline ring in the general formula (I) was replaced with the hydroxyl group at the 3-position is shown in Table 4.
TABLE 4
EC 50: 50% effective concentration (concentration of agent inhibiting 50% of cell death induced by SARS-CoV-2 infection)
CC 50: 50% toxicity concentration (concentration of agent to reduce viable cell count of uninfected cells by 50%)
As is clear from tables 1 to 3, the compounds represented by the formula (I) of the present invention have SARS-CoV-2-inhibiting effects. On the other hand, as is clear from Table 4, even in the case of the compound having a basic skeleton similar to the compound represented by the above formula (I) of the present invention but having a different substitution position of the hydroxyl group, a sufficient SARS-CoV-2-resisting effect was not observed.
EXAMPLE 2 Effect on SARS-CoV-2 mutant strain and the like
From the compounds of the present invention, 4 kinds of derivatives showing a strong anti-SARS-CoV-2 effect in VeroE6/TMPRSS2 cells were selected, and the anti-SARS-CoV-2 effect was examined using cells other than VeroE6/TMPRSS 2. As a result, the HEK293T/ACE2 cells derived from human showed strong effects. In particular YMSA-0785 show the following effects: the 50% effective concentration (EC 50) was 0.12. Mu.M, the 50% toxic concentration (CC 50) > 100. Mu.M, the selection factor (CC 50/EC50) >833 (Table 5).
These agents also have SARS-CoV-2-resistant effects on the mutant strain equivalent to those of the standard strain (Table 5).
TABLE 5
The upper row of values represents EC 50 (μm) and the lower row represents CC 50 (μm).
The measurement in HEK293T/ACE2 cells was performed in the following manner.
(Assay in HEK293T/ACE2 cells)
(1) Cell viability assay (absorbance)
HEK293T/ACE2 cells (2X 10 4 cells/well) were seeded on microplates with 100. Mu.L of cell culture broth. After culturing for 24 hours, each of the reagents obtained by diluting the reagent stock solution to a concentration 4 times the final concentration was added to each well at 50. Mu.L per well, and further 50. Mu.L of a virus solution (an infection plate) was added to SARS-CoV-2 (strain WK-521) (obtained from national infection institute) at MOI=0.1. Each of the reagents obtained by diluting the reagent stock solution to a concentration 4 times the final concentration was added to each well of the cell plate at 50. Mu.L per well, and then 50. Mu.L of the cell culture solution was added. After 3 days of incubation, the culture supernatant of the plates for infection was transferred to a new plate and stored at-80 ℃. mu.L of the culture medium of the cell plate was discarded, and 10. Mu.L of Cell Counting Kit-8 was added. After 2 hours of incubation in a CO 2 incubator, the measurement was performed at 450nm (620 nm).
(2) QPCR assay of viral RNA in culture supernatant
To 50. Mu.L of the culture supernatant was added 50. Mu.L of LDNA/RNA SHIELD (Zymo Research), and RNA extraction (15. Mu.L) was performed using Quick-RNA visual 96kit (Zymo Research) according to the instructions. The extracted RNA was diluted 10-fold with Nuclease-free water (nucleic-FREE WATER) to prepare an RNA sample. For RNA samples, cDNA was synthesized using the High-CAPACITY RNA-to-cDNA TM Kit (Thermo FISHER SCIENTIFIC), and then the measurement of RNA in the samples was performed by the real-time PCR method.
EXAMPLE 3 Synthesis of YMSA-0398 hydrochloride
[ Chemical formula 3]
YMSA-0398 hydrochloride
Using a microwave synthesis apparatus (Discover, CEM, 50W), 4-chloroquinazoline (144 mg,0.88 mmol) was reacted with a solution of 4-aminophenol (99 mg,1.2 mmol) in EtOH (5 mL) at 80℃for 50 minutes. After allowing the reaction solution to warm to room temperature, et 2 O (5 mL) was added, and the precipitated solid was filtered off and washed with diethyl ether. The resulting solid was recrystallized from Et 2 O/MeOH to give YMSA-0398 hydrochloride (120 mg, 43%) as a pale yellow green powder. mp 284-290 ℃.
EXAMPLE 4 Synthesis of YMSA-0329 hydrochloride
[ Chemical formula 4]
YMSA-0329 hydrochloride
Using a microwave reaction apparatus (Discover, CEM, 50W), 4-chloroquinazoline (119 mg,0.73 mmol) was reacted with a solution of 4-amino-2-fluorophenol (93 mg,0.73 mmol) in EtOH (5 mL) at 80℃for 60 minutes. After allowing the reaction solution to warm to room temperature, et 2 O (5 mL) was added, and the precipitated solid was filtered off and washed with diethyl ether. The resulting solid was recrystallized from Et 2 O/MeOH to give YMSA-0329 hydrochloride (117 mg, 63%) as a yellowish green powder. mp 249-265 ℃.
EXAMPLE 5 Synthesis of YMSA-0721 hydrochloride
[ Chemical formula 5]
YMSA-0721 hydrochloride
Using a microwave reaction apparatus (Discover, CEM, 50W), 4-chloroquinazoline (189 mg,1.2 mmol) was reacted with a solution of 4-amino-2-chlorophenol (164 mg,1.1 mmol) in EtOH (5 mL) at 80℃for 60min. After allowing the reaction solution to warm to room temperature, et 2 O (5 mL) was added, and the precipitated solid was filtered off and washed with diethyl ether. The resulting solid was recrystallized from MeOH to give YMSA-0721 hydrochloride (176 mg, 65%) as a yellow powder. mp 284-290 ℃.
EXAMPLE 6 Synthesis of YMSA-0840 hydrochloride
[ Chemical formula 6]
YMSA-0840 hydrochloride
A mixture of 4-chloroquinazoline (134 mg,0.81 mmol) and 4-amino-2-bromophenol (153 mg,0.82 mmol) was reacted in EtOH (5 mL) at 80℃for 60 min using a microwave reaction apparatus (Discover, CEM, 50W). After allowing the reaction solution to warm to room temperature, et 2 O (5 mL) was added, and the precipitated solid was filtered off and washed with diethyl ether. The resulting solid was recrystallized from EtOH to give YMSA-08401.25 hydrochloride (96 mg, 37%) as a yellow powder. mp 277-288 ℃.
EXAMPLE 7 Synthesis of YMSA-0414 hydrochloride
[ Chemical formula 7]
YMSA-0414 hydrochloride
A mixture of 4-chloroquinazoline (91 mg,0.56 mmol) and 4-amino-2-iodophenol (133 mg,0.56 mmol) was reacted in EtOH (5 mL) at 80℃for 60 min using a microwave reaction apparatus (Discover, CEM, 50W). After allowing the reaction solution to warm to room temperature, et 2 O (5 mL) was added, and the precipitated solid was filtered off and washed with diethyl ether. The resulting solid was recrystallized from MeOH to give YMSA-0414 hydrochloride (104 mg, 51%) as a yellow powder. mp 250-255 ℃.
EXAMPLE 8 Synthesis of YMSA-0891 hydrochloride
[ Chemical formula 8]
YMSA-0891 hydrochloride
A mixture of 4-chloroquinazoline (119 mg,0.73 mmol) and 5-amino-2-chlorophenol (103 mg,0.72 mmol) was reacted in EtOH (5 mL) at 80℃for 60 min using a microwave reaction apparatus (Discover, CEM, 50W). After allowing the reaction solution to warm to room temperature, et 2 O (5 mL) was added, and the precipitated solid was filtered off and washed with diethyl ether. The resulting solid was recrystallized from MeOH to give YMSA-0891 hydrochloride (118 mg, 60%) as a yellow powder. mp 287-289 ℃.
EXAMPLE 9 Synthesis of YMSA-0464
[ Chemical formula 9]
2- ((Diethylamino) methyl) -4-nitrophenol (2)
Diethylamine (8.6 mL,83.5 mmol) and 37% aqueous hcho (8.5 mL,0.10 mol) were added to a solution of 4-nitrophenol 1 (2.9 g,20.8 mmol) in EtOH (100 mL) and heated to reflux for 44 hours. After the reaction, the reaction solution was concentrated under reduced pressure, H 2 O (50 mL) was added, and extraction was performed with AcOEt (50 mL. Times.3). The combined organic phases were washed with saturated brine, dried over Na 2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/acoet=1/1 to 1/3), to obtain compound 2 (3.5 g, 76%) as a yellow oily substance.
2- ((Diethylamino) methyl) -6-iodo-4-nitrophenol (YMSA-0532)
N-iodosuccinimide (1.6 g,7.3 mmol) was added to a solution of 2 (1.6 g,7.3 mmol) in MeCN (35 mL) and stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (hexane/acoet=1/1 to 1/2). To the resulting compound was added hexane/CHCl 3, and after insoluble matter was filtered off, the filtrate was concentrated under reduced pressure to obtain compound 3 (1.2 g, 47%) as a yellow solid. mp118 ℃ (dec.).
4-Amino-2- ((diethylamino) methyl) -6-iodophenol (3)
SnCl 2·2H2 O (0.31 g,1.4 mmol) was added to a solution of YMSA-0532 (96 mg,0.27 mmol) in EtOH (8 mL) and the reaction solution was heated to reflux for 1.5 h. The reaction solution was concentrated under reduced pressure, saturated aqueous NaHCO 3 (30 mL) was added, and extraction was performed with AcOEt (30 mL. Times.3). The combined organic phases were washed with saturated brine, dried over Na 2SO4, filtered and concentrated under reduced pressure to give compound 3 (82.6 mg, 90%) as a yellow solid. mp 69 ℃ (dec.).
YMSA-0464
Compound 3 (36 mg,0.11 mmol) was added to a solution of 4-chloroquinazoline (4) (18 mg,0.11 mmol) in EtOH (1 mL) and the reaction solution was heated to reflux for 3 h. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/acoet=1/1). The oily substance obtained was solid by Et 2 O/MeOH, and was obtained as a beige powdery substance YMSA-0464(5.5mg,11％).mp 185-189℃.IR(ATR):ν＝2971,1618,1572,1533,1497,1444,1387,1353,1319,1284,1246,1169,1115,1067,1049,997,956,908,876,816,765,680,671,637,591,581,564,512,502,473,463,434,414cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.73(s,1H),7.90-7.81(m,4H),7.56(t,J＝6.9Hz,1H),7.43(d,J＝2.7Hz,1H),3.81(s,2H),2.68(q,J＝7.2Hz,4H),1.15(t,J＝7.2Hz,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝157.8,155.6,155.2,150.0,133.0,132.1,130.1,129.1,126.7,123.7,122.1,120.3,115.0,84.6,57.0,46.3,11.1ppm.HRMS(FAB+):calcd for[M+H]+,C19H22IN4O:449.0838;found 449.0839.Anal.Calcd(％)for C19H21IN4O:C,50.90;H,4.72;N,12.50.found:C,50.51;H,4.63;N,12.33.
EXAMPLE 10 Synthesis of YMSA-0514
[ Chemical formula 10]
SnCl 2·2H2 O (0.25 g,1.1 mmol) was added to a solution of YMSA-0532 (80 mg,0.22 mmol) in EtOH (4 mL) and the reaction solution was heated to reflux for 30min. To this was added 2-bromoquinoxaline (5) (36 mg,0.22 mmol), and the mixture was heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (CHCl 3/meoh=50/1 to 10/1). The oily substance obtained was obtained as a solid as a yellow powdery substance using Et 2 O/MeOH YMSA-0514(98mg,97％).mp 37-40℃.IR(ATR):ν＝3303,2969,2930,1668,1611,1582,1543,1459,1412,1386,1349,1287,1228,1191,1163,1112,1044,1019,991,953,928,907,864,807,756,715,660,636,597,547,504,414cm-1.1H NMR(399MHz,CDCl3/TMS):δ＝8.34(s,1H),7.92-7.89(m,2H),7.75(dd,J＝8.6,1.2Hz,1H),7.62(td,J＝6.8,1.2Hz,1H),7.45(td,J＝7.8,1.2Hz,1H),7.33(d,J＝1.8Hz,1H),6.66(brs,1H),3.78(s,2H),2.67(q,J＝7.2Hz,4H),1.14(t,J＝7.2Hz,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝155.0,149.8,137.9,131.2,130.7,130.4,128.9,126.8,125.5,122.4,122.2,116.5,84.9,57.0,46.4,46.3,11.1ppm.HRMS(FAB+):calcd for[M+H]+,C19H22IN4O:449.0833;found 449.0834.Anal.Calcd(％)for C20H13IN4O·0.3H2O,0.1AcOEt:C,51.42;H,5.16;N,11.76.found:C,51.45;H,5.04;N,11.47.
EXAMPLE 11 Synthesis of YMSA-0516
[ Chemical formula 11]
2-Bromo-6- ((diethylamino) methyl) -4-nitrophenol (6)
Compound 6 (0.16 g, 50%) was obtained as a yellow solid from compound 2 and N-bromosuccinimide (NBS) using the same method as the synthesis of YMSA-0532. mp 148 ℃ (dec.).
YMSA-0516
Obtained as a yellow solid by the same method as YMSA-0514 YMSA-0516(0.11g,88％).mp 181-185℃.IR(ATR):ν＝2975,1619,1573,1534,1497,1465,1403,1354,1319,1287,1247,1224,1184,1119,1069,1051,998,957,917,875,854,817,765,723,676,639,592,584,566,514,464,437,423,408cm-1.1H NMR(399MHz,DMSO-d6/TMS):δ＝8.73(s,1H),7.91(d,J＝8.0Hz,1H),7.85-7.78(m,2H),7.71(d,J＝2.0Hz,1H),7.55(t,J＝7.2Hz,1H),7.35(d,J＝2.0Hz,1H),7.30(s,1H),3.82(s,2H),2.67(q,J＝6.8Hz,4H),1.14(t,J＝6.8Hz,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝157.9,155.1,153.1,150.0,133.0,129.6,129.0,126.7,126.4,123.1,122.5,120.4,115.0,110.0,57.0,46.4,11.1ppm.HRMS(FAB+):calcd for[M+H]+,C19H22BrN4O:401.0977;found 401.0976.Anal.Calcd(％)for C19H21BrN4O·0.2H2O:C,56.36;H,5.33;N,13.84.found:C,56.34;H,5.09;N 13.50.
EXAMPLE 12 Synthesis of YMSA-0517
[ Chemical formula 12]
Obtained as a yellow powdery substance by the same method as in the synthesis of YMSA-0514 YMSA-0517(53mg,69％).mp 125℃(dec.).IR(ATR):ν＝2971,1622,1579,1504,1456,1430,1335,1240,1218,1145,1112,1072,1030,1004,914,846,804,748,687,661,568,557,508,465,420cm-1.1H NMR(300MHz,DMSO-d6/TMS):δ＝8.77(s,1H),8.23(s,1H),8.13(d,J＝2.4Hz,1H),7.85(d,J＝2.4Hz,1H),7.30(s,1H),4.34(s,2H),4.01(s,3H),3.99(s,3H),3.13(q,J＝6.9Hz,4H),1.28(t,J＝6.9Hz,6H)ppm.13C NMR(100MHz,DMSO-d6/TMS):δ＝157.5,155.2,155.1,154.1,149.9,147.9,132.8,132.3,124.6,123.1,109.8,108.3,102.9,85.0,57.3,57.2,56.9,46.7,12.0ppm.HRMS(FAB+):calcd for[M+H]+,C21H26IN4O3:509.1050;found 509.1050.Anal.Calcd(％)for C21H25IN4O3·0.5H2O:C,48.05;H,5.07;N,10.83.found:C,48.37;H,4.74;N,10.62.
EXAMPLE 13 Synthesis of YMSA-0576
[ Chemical formula 13]
2- ((4-Methylpiperazin-1-yl) methyl) -4-nitrophenol (14)
Compound 14 (0.50 g, 67%) was obtained as a yellow oily substance by the same method as the synthesis of compound 2.
2-Iodo-6- ((4-methylpiperazin-1-yl) methyl) -4-nitrophenol (15)
Compound 15 (0.17 g, 38%) was obtained as a yellow solid by the same method as the synthesis of YMSA-0532. mp 148 ℃ (dec.).
YMSA-0576
Obtained as a yellow solid by the same method as YMSA-0514 YMSA-0576(24mg,34％).mp 190℃(dec.).IR(ATR):ν＝2938,2795,1619,1589,1567,1529,1499,1442,1433,1410,1390,1356,1342,1321,1302,1281,1240,1157,1134,1117,1087,1075,1050,1005,987,924,913,885,867,815,801,775,724,681,653,631,596,580,567,528,508,488,469,432,428cm-1.1H NMR(399MHz,CDCl3/TMS):δ＝8.73(s,1H),7.93-7.90(m,2H),7.85-7.79(m,2H),7.76(t,J＝6.8Hz,1H),7.44(d,J＝2.4Hz),7.28(brs,1H),3.74(s,2H),2.60(brs,8H),2.32(s,3H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝157.7,155.0,154.7,149.9,133.0,132.2,130.4,129.0,126.6,123.8,121.2,120.1,114.8,84.4,61.4,54.6,52.4,45.8ppm.HRMS(FAB+):calcd for[M+H]+,C20H23IN5O:476.0947;found 479.0946.Anal.Calcd(％)for C20H22IN5O·0.5H2O:C,49.60;H,4.79;N,14.46.found:C,49.54;H,4.76;N,14.45.
EXAMPLE 14 Synthesis of YMSA-0613
[ Chemical formula 14]
2- ((Ethylamino) methyl) -4-nitrophenol (20)
70% Aqueous ethylamine (85. Mu.L, 1.0 mmol) was added to a solution of 5-nitrosalicylaldehyde (0.17 g,1.0 mmol) in MeOH (5 mL). After stirring the reaction solution at room temperature for 1 hour, a solution of NaBH 4 (44 mg,1.2 mmol) in MeOH (3 mL) was added and stirred at room temperature for 1 hour. The resulting solid was filtered off and washed with MeOH to give compound 20 (0.16 g, 79%) as a yellow powder. mp 209-210 ℃.
2- ((Ethylamino) methyl) -6-iodo-4-nitrophenol (21)
To a solution of compound 20 (0.10 g,0.50 mmol) in MeCN was added 1N aqueous HCl (10 drops) until the reaction became colorless, and NIS (0.13 g,0.57 mmol) was further added and stirred at room temperature for 30 minutes. The reaction was quenched with saturated aqueous NaHCO 3 and the pH was adjusted to 7. The resulting solid was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (CHCl 3/meoh=10/1) to give compound 21 (0.17 g, 100%) as a yellow solid. mp 145 ℃ (dec.).
YMSA-0613
Obtained as a yellow powdery substance by the same method as in the synthesis of YMSA-0514 YMSA-0613(18mg,28％).mp 115℃(dec.).IR(ATR):ν＝2970,1618,1576,1516,1463,1392,1357,1318,1125,1073,918,868,765,681,570,470,418,407cm-1.1H NMR(399MHz,CDCl3/TMS):δ＝8.72(s,1H),7.91(d,J＝8.4Hz,1H),7.85-7.78(m,3H),7.55(t,J＝8.4Hz,1H),7.43(s,1H),4.01(s,2H),2.77(q,J＝8.4Hz,2H),1.20(t,J＝7.6Hz,3H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝155.5,155.0,149.9,132.8,132.2,130.0,129.0,126.6,123.8,122.5,120.2,114.9,84.8,52.5,43.1,14.7ppm.HRMS(FAB+):calcd for[M+H]+,C17H18IN4O:421.0525;found 421.0526.Anal.Calcd(％)for C17H17IN4O·0.1AcOEt:C,48.71;H,4.18;N,13.06.found:C,48.58;H,.4.31;N,12.81.
EXAMPLE 15 Synthesis of YMSA-0614
[ Chemical formula 15]
2- ((Ethyl (methyl) amino) methyl) -4-nitrophenol (22)
Compound 22 (0.75 g, 71%) was obtained as a yellow solid by the same method as the synthesis of compound 2. mp 48-51 ℃.
2- ((Ethyl (methyl) amino) methyl) -6-iodo-4-nitrophenol (23)
Compound 23 (0.41 g, 81%) was obtained as a yellow solid using the same method as the synthesis of YMSA-0532. mp 121-131 ℃.
YMSA-0614
Obtained as a yellow solid by the same method as the synthesis of YMSA-0464 YMSA-0614(55mg,85％).mp 163℃(dec.).IR(ATR):ν＝2967,1618,1572,1531,1497,1452,1389,1355,1318,1223,1166,1074,1029,913,867,818,762,725,677,573,560,466,440,419cm-1.1H NMR(399MHz,CDCl3/TMS):δ＝8.72(s,1H),7.91(d,J＝8.4Hz,1H),7.87-7.85(m,2H),7.80(t,J＝8.0Hz,1H),7.55(t,J＝6.3Hz,1H),7.41(d,J＝2.4Hz,1H),7.38(brs,1H),2.61(q,J＝7.2Hz,2H),2.32(s,2H),1.17(t,J＝7.2Hz,3H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝156.7,154.3,154.0,148.9,131.9,131.1,129.1,127.9,125.6,122.6,120.8,119.3,113.6,83.5,59.7,49.7,39.5,10.9ppm.HRMS(FAB+):calcd for[M+H]+,C18H20IN4O:435.0682;found 435.0682.Anal.Calcd(％)for C18H19IN4O·0.3AcOEt:C,50.06;H,4.68;N,12.16.found:C,49.90;H,4.42;N,11.91.
EXAMPLE 16 Synthesis of YMSA-0636
[ Chemical formula 16]
YMSA-0635
Compound 3 (76 mg,0.24 mmol) and N, N-Diisopropylethylamine (DIEA) (45. Mu.L, 0.25 mmol) were added to a solution of 2, 4-dichloroquinazoline 28 (34 mg,0.17 mmol) in DMF (2 mL). After stirring the reaction solution for 2.5 hours, H 2 O (20 mL) was added and extracted with EtOAc (20 mL. Times.3). The combined organic phases were washed with saturated brine, dried over Na 2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (CHCl 3/meoh=100/1), and solidified with hexane to give a beige solid YMSA-0635(45mg,54％).mp 183-185℃.IR(ATR):ν＝3263,2969,2848,2930,1616,1567,1528,1494,1446,1388,1365,1354,1340,1278,1249,1195,1167,1116,1982,1067,1048,997,948,906,875,854,815,787,761,723,686,676,639,598,571,517,503,473,407cm-1.1H NMR(399MHz,CDCl3/TMS):δ＝7.82-7.79(m,4H),7.55-7.48(m,3H),3.78(s,2H),2.67(q,J＝7.2Hz,4H),1.14(t,J＝7.2Hz,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝158.7,157.4,155.9,151.4,133.9,131.5,129.5,128.3,126.8,123.3,122.1,120.6,113.3,84.4,56.9,46.3,11.0ppm.HRMS(FAB+):calcd for[M+H]+,C19H21IClN4O:483.0449;found 483.0449.Anal.Calcd(％)for C19H20ClIN4O:C,47.27;H,4.18;N,11.61.found:C,47.40;H,4.12;N,11.46.
YMSA-0636
Dimethylamine hydrochloride (80 mg,0.98 mmol) and NEt 3 (0.17 mL,1.2 mmol) were added to a solution of YMSA-0635 (0.12 g,0.25 mmol) in EtOH (5 mL). After the reaction solution was heated under reflux for 4 hours, water (20 mL) was added and extracted with EtOAc (20 mL. Times.3). The combined organic phases were washed with saturated brine, dried over Na 2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (AcOEt), and solidified with hexane/CHCl 3 to obtain a pale yellow solid YMSA-0636(91mg,75％).mp 168-176℃.IR(ATR):ν＝2969,1620,1580,1559,1523,1459,1379,1305,1259,1191,1160,1122,1087,1042,1019,877,861,805,790,759,719,674,651,635,562,509,433,408cm-1.1H NMR(399MHz,CDCl3/TMS):δ＝8.14(d,J＝2.4Hz,1H),7.60(d,J＝8.0Hz,1H),7.52-7.51(m,2H),7.28(d,J＝2.0Hz,1H),7.18(brs,1H),7.07(td,J＝7.2,1.6Hz,1H),3.71(s,2H),3.23(s,6H),2.63(q,J＝7.2Hz,4H),1.10(t,J＝7.2Hz,6H)ppm.HRMS(FAB+):calcd for[M+H]+,C21H27IN5O:492.1260;found 492.1258.Anal.Calcd(％)for C21H26IN5O·0.1CHCl3:C,50.35;H,5.23;N,13.91.found:C,50.59;H,4.98;N,13.66.
EXAMPLE 17 Synthesis of YMSA-0656
[ Chemical formula 17]
2-Chloro-6- ((diethylamino) methyl) -4-nitrophenol (29)
In the same manner as in the synthesis of YMSA-0532, compound 2 was reacted with N-chlorosuccinimide to obtain compound 29 (1.1 g, 69%) as a yellow powder solid. mp142-150 ℃.
YMSA-0656
Obtained as a yellow solid by the same method as YMSA-0464 YMSA-0656(90mg,42％).mp 170-174℃.IR(ATR):ν＝2969,1617,1572,1532,1469,1405,1354,1318,1246,1227,1190,1165,1125,1072,959,919,867,818,761,725,677,587,570,545,517,465,438,424cm-1.1H NMR(399MHz,CDCl3/TMS):δ＝8.71(s,1H),7.97(d,J＝8.4Hz,1H),7.90-7.86(m,2H),7.77(t,J＝7.2Hz,1H),7.53(d,J＝2.4Hz,1H),7.50(t,J＝7.2Hz,1H),7.22(d,J＝2.0Hz,1H),3.75(s,2H),2.62(q,J＝7.6Hz,4H),1.09(t,J＝7.6Hz,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝158.4,155.4,150.2,133.4,129.6,129.0,127.0,124.1,123.5,122.2,121.2,121.0,115.4,57.2,46.7,11.4ppm.HRMS(ESI+):calcd for[M+H]+,C19H22ClN4O:357.1477;found 357.1472.Anal.Calcd(％)for C19H21ClN4O·0.03CHCl3:C,63.41;H,5.88;N,15.54.found:C,63.78;H,5.53;N,15.19.
EXAMPLE 18 Synthesis of YMSA-0707
[ Chemical formula 18]
4-Amino-2-chloro-6- ((diethylamino) methyl) phenol (32)
Compound 32 (0.33 g, 59%) was obtained as a yellow oily substance by the same method as the synthesis of compound 3.
2-Chloro-4- ((2-chloroquinazolin-4-yl) amino) -6- ((diethylamino) methyl) phenol (33)
Compound 33 (0.11 g, 55%) was obtained as a pale yellow powder solid by the same method as the synthesis of YMSA-0635. mp 90-99 ℃.
YMSA-0707
Obtained as a pale yellow solid by the same method as in the synthesis of YMSA-0636 YMSA-0707(38mg,46％).mp 176-180℃.IR(ATR):ν＝3304,3133,3054,2972,2937,1622,1581,1558,1528,1464,1383,1350,1303,1264,1250,1228,1191,1165,1125,1106,1089,1063,1045,1019,996,926,875,853,807,793,780,771,742,719,663,635,584,566,549,538,508,483,426,407cm-1.1H NMR(399MHz,CDCl3/TMS):δ＝7.76(d,J＝2.8Hz,1H),7.59(d,J＝8.0Hz,1H),7.52(td,J＝7.4,2.0Hz,2H),7.23(d,J＝2.4Hz,1H),7.11-7.07(m,2H),3.78(s,2H),3.24(s,6H),2.65(q,J＝7.2Hz,4H),1.13(t,J＝7.2Hz,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝159.4,157.3,153.1,150.7,132.8,130.4,126.2,123.0,122.4,121.0,120.4,110.0,56.9,46.4,37.2,11.1ppm.HRMS(FAB+):calcd for[M]+,C21H26ClN5O:399.1826;found 399.1826.Anal.Calcd(％)for C21H26ClN5O·0.2AcOEt:C,62.71;H,6.66;N,16.77.found:C,62.83;H,6.41;N,16.56.
EXAMPLE 19 Synthesis of YMSA-0781
[ Chemical formula 19]
2- ((Diisopropylamino) methyl) -4-nitrophenol (40)
Diisopropylamine (0.26 mL,1.8 mmol) and Et 3 N (0.42 mL,3.0 mmol) were added to a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.35 g,1.5 mmol) in THF (7 mL), and the reaction solution was heated to reflux for 30min. The reaction solution was concentrated under reduced pressure, and the remaining residue was dissolved in AcOEt (20 mL) and washed with H 2 O (20 mL. Times.3) and saturated brine (20 mL). The organic phase was dried over Na 2SO4, filtered and concentrated under reduced pressure to give compound 40 (0.33 g, 88%) as a yellow solid. mp 112-115 ℃.
2- ((Diisopropylamino) methyl) -6-iodo-4-nitrophenol (41)
Compound 41 (0.24 g, 75%) was obtained as a yellow solid using the same method as the synthesis of YMSA-0532. mp 151-153 ℃.
YMSA-0781
Obtained as a pale yellow solid by the same method as in the synthesis of YMSA-0464 YMSA-0781(15mg,47％).mp 111-120℃.IR(ATR):ν＝2968,1619,1571,1530,1498,1465,1390,1369,1315,1239,1192,1169,1118,1073,948,914,869,819,764,735,707.680,569,551,498,467,432,419cm-1.1H NMR(399MHz,CDCl3/TMS):δ＝8.73(s,1H),7.91(d,J＝8.4Hz,1H),7.86-7.78(m,3H),7.55(td,J＝7.4,1.2Hz,1H),7.41(d,J＝2.8Hz,1H),7.35(brs,1H),3.85(s,2H),3.21-3.15(m,2H),1.15(d,J＝6.8Hz,12H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝157.9,156.0,155.2,150.0,133.0,131.8,129.9,129.1,126.7,123.5,122.7,120.4,115.0,84.7,49.1,48.4,19.8ppm.HRMS(FAB+):calcd for[M+H]+,C21H26IN4O:477.1151;found 477.1153.Anal.Calcd(％)for C21H25IN4O·0.1H2O:C,52.75;H,5.31;N,11.72.found:C,52.68;H,5.47;N,11.33.
EXAMPLE 20 Synthesis of YMSA-0797
[ Chemical formula 20]
2- ((Cyclohexyl (ethyl) amino) methyl) -4-nitrophenol (43)
Compound 43 (0.52 g, 100%) was obtained as a yellow oily substance by the same method as the synthesis of compound 40.
2-Chloro-6- ((cyclohexyl (ethyl) amino) methyl) -4-nitrophenol (44)
Compound 44 (92 mg, 37%) was obtained as a yellow oily substance by the same method as the synthesis of compound 29.
YMSA-0797
Obtained as a yellow solid by the same method as the synthesis of YMSA-0464 YMSA-0797(35mg,35％).mp 80-85℃.IR(ATR):ν＝2928,2854,1669,1618,1573,1532,1470,1391,1356,1319,1234,1171,1123,1073,967,915,868,765,680,581,533,465,429,416cm-1.1H NMR(399MHz,CDCl3/TMS):δ＝8.72(s,1H),7.91-7.88(m,2H),7.81-7.79(m,2H),7.55-7.53(m,3H),3.87(s,2H),2.66-2.64(m,3H),1.89(d,J＝12Hz,2H),1.82(d,J＝12Hz,2H),1.65(d,J＝13Hz,1H),1.34-1.22(m,4H),1.14(t,J＝6.8Hz,3H),0.89(t,J＝6.8Hz,1H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝157.9,155.1,152.5,149.9,143.6,134.9,133.0,128.9,126.7,123.5,121.7,120.8,120.5,115.0,58.9,53.6,43.9,28.1,26.1,25.9,13.0ppm.HRMS(FAB+):calcd for[M+H]+,C23H28ClN4O:411.1952;found 411.1950.Anal.Calcd(％)for C23H27ClN4O·0.4H2O:C,66.07;H,6.70;N,13.40.found:C,66.04;H,6.64;N,13.10.
EXAMPLE 21 Synthesis of various quinazoline derivatives
[ Chemical formula 21]
2- ((Diisopropylamino) methyl) -6-chloro-4-nitrophenol (48)
To a solution of compound 40 (319 mg,1.26 mmol) dissolved in acetonitrile 10mL was added N-chlorosuccinimide (203 mg,1.52 mmol) and stirred at room temperature for 23 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) and compound 48 (241 mg, 67%) was isolated as a yellow solid. mp 154-157 ℃.
YMSA-0785
To a solution of compound 48 (57 mg,0.20 mmol) dissolved in 5mL of ethanol was added lead chloride dihydrate (0.18 g,0.80 mmol) and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (66 mg,0.40 mmol) was added to the reaction solution, and stirred again under reflux for 3 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) and isolated as a yellow solid YMSA-0785(76mg,quant.).mp 258℃(dec.).IR(ATR):ν＝2971,1619,1590,1569,1528,1472,1446,1421,1390,1355,1315,1292,1250,1195,1147,1119,1074,1016,970,918,899,872,799,787,776,678,647,579,554,526,507,465,450,428,405cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.74(s,1H),7.93-7.90(m,1H),7.84-7.78(m,2H),7.59-7.52(m,2H),7.31(d,J＝2.1Hz,1H),3.92(s,2H),3.25-3.19(m,2H),1.16(d,J＝6.7Hz,12H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝158.9,155.7,152.1,150.7,134.1,131.2,128.9,127.3,125.2,124.0,123.8,123.0,119.5,116.2,49.2(2C),49.0,20.5(4C)ppm.HRMS(ESI+):calcd for[M+H]+,C21H26ClN4O:385.1790;found 385.1791.Anal.Calcd(％)for C21H26ClN4O+0.25H2O:C 64.77,H 6.60,N 14.39;found:C 64.93,H 6.55,N 14.07.
2- ((Tert-butyl (isopropyl) amino) methyl) -4-nitrophenol (49)
To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g,1.0 mmol) dissolved in 4mL tetrahydrofuran was added N-t-butylisopropylamine (0.19 mL,1.2 mmol) and triethylamine (0.31 mL,2.2 mmol) and stirred under reflux for 3 hours. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) and compound 49 (0.18 g, 69%) was isolated as a yellow solid. mp 142-147 ℃.
2- ((Tert-butyl (isopropyl) amino) methyl) -6-chloro-4-nitrophenol (50)
To a solution of compound 49 (183 mg,0.69 mmol) dissolved in 5mL of acetonitrile was added N-chlorosuccinimide (101 mg,0.76 mmol), and the mixture was stirred at room temperature for 23 hours. The solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate), and compound 50 (130 mg, 63%) was isolated as a yellow solid. mp 167-172 ℃.
YMSA-0897
To a solution of compound 50 (60 mg,0.20 mmol) dissolved in 2mL of ethanol was added lead chloride dihydrate (0.18 g,0.80 mmol) and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (66 mg,0.40 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) and isolated as a yellow solid YMSA-0897(71mg,89％).mp 170℃(Dec.).IR(ATR):ν＝2970,1732,1620,1601,1572,1537,1500,1476,1431,1414,1392,1372,1356,1323,1309,1288,1239,1195,1172,1146,1125,1077,1027,969,916,886,869,813,797,786,734,699,679,668,584,573,520,497,468,426,417cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.74(s,1H),7.93-7.90(m,1H),7.83-7.78(m,2H),7.58-7.52(m,2H),7.46(d,J＝2.7Hz,1H),4.02(s,2H),3.53(sep,J＝6.6Hz,1H),1.22(s,9H),1.17(d,J＝6.6Hz,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝158.9,155.8,152.1,150.7,134.1,131.1,128.9,127.9,127.3,124.0,123.1,121.4,119.7,116.2,58.3,48.7,46.8,28.3(3C),22.2(2C)ppm.HRMS(ESI+):calcd for[M+H]+,C22H28ClN4O:399.1946;found 399.1945.Anal.Calcd(％)for C22H27ClN4O+0.25CHCl3:C 62.33,H 6.41,N13.07;found:C 62.59,H 6.51,N 12.68.
2- ((Isopropyl (propyl) amino) methyl) -4-nitrophenol (51)
To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g,1.0 mmol) dissolved in 4mL tetrahydrofuran was added N-isopropylpropylamine (0.12 mL,1.2 mmol) and triethylamine (0.31 mL,2.2 mmol) and stirred under reflux for 1 hour. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate), and compound 51 (0.22 g, 88%) was isolated as a yellow oil.
2- ((Isopropyl (propyl) amino) methyl) -6-chloro-4-nitrophenol (52)
To a solution of compound 51 (221 mg,0.88 mmol) dissolved in 5mL of acetonitrile was added N-chlorosuccinimide (175 mg,1.3 mmol), and the mixture was stirred at room temperature for 23 hours. The solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate), and compound 52 (132 mg, 52%) was isolated as a yellow solid. mp 67-68 ℃.
YMSA-0864
To a solution of compound 52 (75 mg,0.26 mmol) dissolved in 3mL of ethanol was added lead chloride dihydrate (0.24 g,1.04 mmol) and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (86 mg,0.52 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) and isolated as a yellow solid YMSA-0864(80mg,79％).mp 72-78℃.IR(ATR):ν＝2967,1620,1574,1534,1499,1393,1358,1319,1237,1168,1125,1074,1027,959,918,871,767,681,583,504,466,430,417,407cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.74(s,1H),7.93-7.90(m,1H),7.83-7.78(m,2H),7.58-7.53(m,2H),7.30(d,J＝2.7Hz,1H),7.21(br,1H),3.85(s,2H),3.13(sep,J＝6.6Hz,1H),2.48(t,J＝7.5Hz,2H),1.61(sext,J＝7.5Hz,2H),1.12(d,6H),0.91(t,J＝7.5Hz,3H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝158.9,155.7,151.8,150.7,134.1,131.4,128.9,127.3,124.8,124.0,123.9,123.1,119.6,116.2,54.1,51.6,50.6,21.6(2C),18.1,12.8ppm.HRMS(ESI+):calcd for[M+2H]+,C21H27ClN4O:193.0931;found 193.0931.Anal.Calcd(％)for C21H26ClN4O+0.25H2O:C 64.77,H 6.60,N 14.39;found:C 64.42,H 6.53,N 14.14.
2- ((Tert-butyl (ethyl) amino) methyl) -4-nitrophenol (53)
To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g,1.0 mmol) dissolved in 4mL tetrahydrofuran was added N-tert-butylethylamine (0.17 mL,1.2 mmol) and triethylamine (0.31 mL,2.2 mmol) and stirred under reflux for 3 hours. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) and compound 53 (0.23 g, 91%) was isolated as a yellow solid. mp 104-109 ℃.
2- ((Tert-butyl (ethyl) amino) methyl) -6-chloro-4-nitrophenol (54)
To a solution of compound 53 (229 mg,0.91 mmol) dissolved in 5mL of acetonitrile was added N-chlorosuccinimide (145 mg,1.1 mmol), and the mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) and compound 54 (124 mg, 48%) was isolated as a yellow solid. mp 145-155 ℃.
YMSA-0823
To a solution of compound 54 (54 mg,0.19 mmol) dissolved in 3mL of ethanol was added lead chloride dihydrate (0.17 g,0.76 mmol) and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (62 mg,0.38 mmol) was added to the reaction solution, and stirred again under reflux for 1.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and isolated as a yellow solid YMSA-0823(66mg,91％).mp 155℃(dec.).IR(ATR):ν＝2963,1619,1598,1573,1533,1500,1472,1411,1391,1356,1321,1288,1239,1197,1123,1076,1028,996,952,916,884,869,820,788,736,704,679,666,583,546,524,510.496,460,427,418cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.74(s,1H),7.93-7.90(m,1H),7.84-7.78(m,2H),7.58-7.50(m,2H),7.30(d,J＝1.5Hz,1H),3.99(s,2H),2.75(br,2H),1.24(s,9H),1.14(t,J＝7.5Hz,3H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝158.9,155.7,152.2,150.7,134.0,131.1,128.9,127.3,126.1,123.9,123.6,121.9,119.8,116.2,57.3,53.4,45.1,27.2(3C),15.4ppm.HRMS(ESI+):calcd for[M+H]+,C21H26ClN4O:385.1790;found 385.1789.Anal.Calcd(％)for C21H26ClN4O+0.02CHCl3:C 65.19,H 6.51,N 14.47;found:C 65.18,H 6.53,N 14.51.
2- ((Ethyl (pent-3-yl) amino) methyl) -4-nitrophenol (55)
To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g,1.0 mmol) dissolved in 4mL tetrahydrofuran was added N-ethyl (-3-pentyl) amine (0.17 mL,1.2 mmol) and triethylamine (0.31 mL,2.2 mmol) and stirred under reflux for 13 hours. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate), and compound 55 (0.28 g, quant.) was isolated as a yellow solid. mp 44-45 ℃.
2- ((Ethyl (pent-3-yl) amino) methyl) -6-chloro-4-nitrophenol (56)
To a solution of compound 55 (266 mg,1.0 mmol) dissolved in 4mL of acetonitrile was added N-chlorosuccinimide (160 mg,1.2 mmol), and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate), and compound 56 (180 mg, 59%) was isolated as a yellow solid. mp 58-68 ℃.
YMSA-0842
To a solution of compound 56 (180 mg,0.59 mmol) dissolved in 6mL of ethanol was added lead chloride dihydrate (0.53 g,2.4 mmol) and stirred under reflux for 1 hour. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was dissolved in 2mL of ethanol, 4-chloroquinazoline 4 (62 mg,0.38 mmol) was added and stirred under reflux for 6.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and isolated as a yellow solid YMSA-0842(82mg,82％).mp 75-80℃.IR(ATR):ν＝2964,2933,2876,1621,1601,1573,1532,1500,1404,1357,1320,1287,1239,1184,1161,1122,1074,1029,972,944,919,868,818,766,737,720,679,661,581,567,524,497,466,425cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.74(s,1H),7.93-7.90(m,1H),7.84-7.78(m,2H),7.58-7.53(m,2H),7.30(d,J＝1.5Hz,1H),3.87(s,2H),2.64-2.51(m,3H),1.68-1.56(m,2H),1.49-1.39(m,2H),1.17(t,J＝6.9Hz,3H),1.00(t,J＝7.5Hz,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝158.9,155.7,151.5,150.7,134.1,131.6,128.9,127.3,125.2,124.0,123.2,119.6,116.2,64.0,54.0,44.0,22.6(2C),14.1,13.0(2C)ppm.HRMS(ESI+):calcd for[M+H]+,C22H28ClN4O:399.1946;found399.1945.Anal.Calcd(％)for C22H27ClN4O+0.5H2O:C 64.77,H 6,92,N 13.73;found:C 64.90,H 6.96,N 13.70.
2- ((Ethyl (cyclopropyl) amino) methyl) -4-nitrophenol (57)
To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g,1.0 mmol) dissolved in 4mL tetrahydrofuran was added N-isopropylpropylamine (0.17 mL,1.2 mmol) and triethylamine (0.31 mL,2.2 mmol) and stirred under reflux for 1 hour. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate), and compound 57 (0.22 g, 88%) was isolated as a yellow oil.
2- ((Ethyl (cyclopropyl) amino) methyl) -6-chloro-4-nitrophenol (58)
To a solution of compound 57 (266 mg,1.0 mmol) dissolved in 5mL of acetonitrile was added N-chlorosuccinimide (175 mg,1.3 mmol) and the mixture was stirred at room temperature for 23 hours. The solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate), and compound 58 (132 mg, 52%) was isolated as yellow amorphous form.
YMSA-0832
To a solution of compound 58 (75 mg,0.26 mmol) dissolved in 3mL of ethanol was added lead chloride dihydrate (0.24 g,1.04 mmol) and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (86 mg,0.52 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) and isolated as a yellow solid YMSA-0832(80mg,79％).mp 140-145℃.IR(ATR):ν＝3061,2975,2480,1620,1573,1535,1499,1482,1464,1447,1357,1320,1297,1262,1249,1224,1185,1125,1075,1031,934,919,870,852,817,796,784,769,722,677,641,596,574,516,465,432,420,411cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.75(s,1H),7.93-7.91(d,J＝7.8Hz,1H),7.84-7.78(m,2H),7.60-7.54(m,2H),7.30(d,J＝2.7Hz,1H),7.25(br,1H),4.02(s,2H),2.76(q,J＝6.9Hz,2H),1.99-1.92(m,1H),1.19(t,J＝6.9Hz,2H),0.66-0.63(m,4H)ppm.13C NMR(75MHz,CDCl3/TMS):δ＝157.7,155.0,151.4,150.0,132.9,129.5,129.0,126.6,123.4(2C),121.3,120.6,120.2,114.9,58.7,48.6,36.3,10.7,6.5(2C)ppm.HRMS(ESI+):calcd for[M+2H]+,C20H22ClN4O:369.1477;found369.1478.Anal.Calcd(％)for C20H21ClN4O+0.2MeOH:C 64.65,H 5.86,N 14.93;found:C 64.96,H 5.83,N 14.56.
2- ((3, 5-Dimethylpiperidin-1-yl) methyl) -4-nitrophenol (59)
To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g,1.0 mmol) dissolved in 4mL tetrahydrofuran was added 3, 5-dimethylpiperidine (0.16 mL,1.2 mmol) and triethylamine (0.31 mL,2.2 mmol) and stirred under reflux for 2.5 hours. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1), and compound 59 (0.28 g, quat.) was isolated as a yellow oil.
2- ((3, 5-Dimethylpiperidin-1-yl) methyl) -6-chloro-4-nitrophenol (60)
To a solution of compound 59 (274 mg,1.0 mmol) dissolved in 5mL of acetonitrile was added N-chlorosuccinimide (160 mg,1.2 mmol), and the mixture was stirred at room temperature for 15 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate), and compound 60 (68 mg, 23%) was isolated as a yellow oil.
YMSA-0863
To a solution of compound 60 (68 mg,0.23 mmol) dissolved in 3mL of ethanol was added lead chloride dihydrate (0.21 g,0.91 mmol) and stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline 4 (75 mg,0.38 mmol) was added to the reaction solution, and the mixture was stirred again under reflux for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and isolated as a yellow solid YMSA-0863(78mg,86％).mp 80-85℃.IR(ATR):ν＝2953,1620,1573,1534,1499,1405,1357,1317,1286,1236,1124,1067,1027,996,961,918,869,820,765,728,680,591,536,499,467,431,418cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.74(s,1H),7.93-7.90(m,1H),7.84-7.81(m,2H),7.61-7.53(m,2H),7.29(d,J＝2.4Hz,1H),3.74(s,2H),2.97-2.94(m,2H),1.80-1.76(m,2H),1.70-1.62(m,2H),1.27-1.26(m,2H),0.87(d,J＝6.3Hz,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝157.9,155.1,151.8,150.0,133.0,129.3,129.0,126.7,123.7,122.9,121.8,120.8,120.5,115.0,62.2,61.7,60.6,41.6,38.3,31.2,22.7,19.4,14.2ppm.HRMS(ESI+):calcd for[M+H]+,C22H26ClN4O:397.1795;found 397.1784.Anal.Calcd(％)for C22H25ClN4O+0.5H2O:C 65.10,H 6.46,N 13.80;found:C 65.02,H 6.48,N 13.50.
YMSA-0907
To a solution of compound 48 (57 mg,0.2 mmol) dissolved in 3mL of ethanol was added lead chloride dihydrate (0.18 g,0.80 mmol) and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloro-7-fluoroquinazoline 61 (73 mg,0.38 mmol) was added to the reaction solution, and stirred again under reflux for 5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and isolated as a yellow solid YMSA-0907(74mg,91％).mp 170-175℃.IR(ATR):ν＝2974,1625,1600,1576,1529,1457,1444,1425,1394,1344,1322,1287,1202,1149,1113,1072,1010,962,910,839,808,788,722,672,651,602,581,556,533,493,478,439,422cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.70(s,1H),7.87-7.82(m,1H),7.56-7.49(m,2H),7.34-7.28(m,2H),7.20(s,1H),3.92(s,2H),3.21(sep,J＝6.6Hz,2H),1.16(d,J＝6.6Hz,12H)ppm.13C NMR(75MHz,CDCl3/TMS):δ＝157.7,156.1,152.7,128.6,123.7,123.5,123.1,123.0,121.6,120.6,116.4,116.1,113.2,112.9,48.8,48.3(2C),19.6(4C)ppm.HRMS(ESI+):calcd for[M+H]+,C21H25ClFN4O:403.1695;found 403.1695.Anal.Calcd(％)for C21H24ClN4OF:C 62.66,H 6.01,N 13.93;found:C 62.35,H 5.86,N 13.65.
Example 22 Synthesis of YMSA-0808 and YMSA-0644
[ Chemical formula 22]
2- ((Ethyl (isopropyl) amino) methyl) -4-nitrophenol (62)
To a solution of 4-nitrophenol 1 (1.39 g,10.00 mmol) in 8mL of ethanol was added ethyl isopropylamine (1.80 mL,15.0 mmol) and 37% aqueous formaldehyde (1.1 mL,15.0 mmol) and stirred under reflux for 16 h. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate), and compound 62 (414 mg, 15%) was isolated as a yellow solid. mp 65-67 ℃.
2- ((Ethyl (isopropyl) amino) methyl) -6-chloro-4-nitrophenol (63)
To a solution of compound 62 (0.41 g,1.74 mmol) dissolved in 5mL of acetonitrile was added N-chlorosuccinimide (0.46 g,2.5 mmol) and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate: methanol=9:1), and compound 63 (172 mg, 36%) was isolated as a yellow solid. mp 158-164 ℃.
2- ((Ethyl (isopropyl) amino) methyl) -6-iodo-4-nitrophenol (64)
To a solution of compound 62 (0.18 g,0.63 mmol) dissolved in 5mL of acetonitrile was added N-iodosuccinimide (0.21 g,0.94 mmol), and the mixture was stirred at room temperature for 22 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate: methanol=9:1), and compound 64 (213 mg, 83%) was isolated as a yellow solid. mp 145-155 ℃.
YMSA-0808
To a solution of compound 63 (172 mg,0.63 mmol) dissolved in 6mL of ethanol was added lead chloride dihydrate (0.57 g,2.52 mmol) and stirred under reflux for 1 hour. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was dissolved in 1mL of ethanol, 4-chloroquinazoline 4 (16.5 mg,0.10 mmol) was added and stirred under reflux for 3 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate: methanol=9:1) and isolated as a yellow solid YMSA-0808(21.5mg,58％).mp 70-75℃.IR(ATR):ν＝2969,1620,1573,1532,1499,1393,1356,1319,1236,1192,1170,1123,1073,1023,966,918,869,766,720,681,581,565,535,492,465,427,409cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.73(s,1H),7.92-7.77(m,3H),7.56-7.51(m,2H),7.43(br,1H),3.82(s,2H),3.15(sep,J＝6.6Hz,1H),2.59(q,J＝7.2Hz,2H),1.18-1.11(m,9H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝158.9,155.7,152.0,150.7,134.1,131.4,128.9,127.3,124.7,124.0,123.1,119.6,116.2,53.4,50.4,43.9,18.2,14.1ppm.HRMS(ESI+):calcd for[M+2H]+,C20H25ClN4O:186.0853;found 186.0853.Anal.Calcd(％)for C20H23ClN4O+0.75CH3OH:C 63.11,H 6.64,N 14.19;found:C 63.19,H 6.28,N 14.02.
YMSA-0644
To a solution of compound 64 (210 mg,0.51 mmol) dissolved in 10mL of ethanol was added lead chloride dihydrate (0.46 g,2.05 mmol) and stirred under reflux for 2 hours. After cooling to room temperature, 4-chloroquinazoline 4 (170 mg,1.03 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) and isolated as a yellow solid YMSA-0644(173.2mg,73％).mp 155℃(dec.).IR(ATR):ν＝2972,1620,1574,1536,1499,1457,1409,1384,1354,1321,1287,1249,1227,1171,1114,1064,995,960,918,880,858,809,786,767,750,719,640,592,583,570,556,513,503,464,436,421cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.73(s,1H),7.93-7.77(m,4H),7.58-7.52(m,1H),7.41(d,J＝2.7Hz,1H),3.81(s,2H),3.15(sep,J＝6.6Hz,1H),2.60(q,J＝7.2Hz,2H),1.18-1.11(m,9H)ppm.13C NMR(75MHz,CDCl3/TMS):δ＝157.9,155.7,155.0,149.8,132.9,132.0,129.9,128.7,126.5,123.7,122.1,120.5,114.9,84.6,52.9,49.4,43.1,17.3(2C),12.8ppm.HRMS(ESI+):calcd for[M+2H]+,C20H25IN4O:232.0531;found 232.0531.Anal.Calcd(％)for C20H23IN4O+0.25H2O:C 51.46,H 5.07,N 12.00;found:C 51.56,H 4.96,N 11.72.
EXAMPLE 23 Synthesis of Compounds (YMSA-0843 and YMSA-0850) in which the hydroxyl group at the 4-position of the substituted phenylamino group at the 4-position of the quinazoline ring in formula (I) is replaced with the hydroxyl group at the 3-position
[ Chemical formula 23]
To a solution of YMSA-0891 (54 mg,0.2 mmol) in 8mL of ethanol was added diethylamine (82. Mu.L, 0.8 mmol) and 37% aqueous formaldehyde (60. Mu.L, 0.8 mmol) and stirred under reflux for 5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel column chromatography (ethyl acetate) to isolate YMSA-0843 (18.6 mg, 26%) and YMSA-0850(35.6mg,50％).mp 195℃(dec.).IR(ATR):ν＝2963,2923,2838,2580,1613,1579,1558,1538,1500,1415,1375,1359,1330,1314,1282,1241,1210,1165,1151,1125,1080,1059,1038,977,932,886,846,820,799,779,707,685,674,646,596,567,539,514,502,468,453,426cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.69(s,1H),7.94-7.91(m,2H),7.84-7.79(m,1H),7.59-7.54(m,1H),7.29(d,J＝8.4Hz,1H),3.84(s,2H),2.62(q,J＝7.2Hz,4H),1.12(t,J＝7.2Hz,6H)ppm.13C NMR(75MHz,CDCl3/TMS):δ＝158.6,155.1,153.7,150.0,136.6,133.0,128.9,128.4,126.6,121.2,118.3,118.1,116.1,115.4,51.4,46.5(2C),11.0(2C)ppm.HRMS(ESI+):calcd for[M+H]+,C19H22N4O:357.1477;found 357.1477.Anal.Calcd(％)for C19H21N4O+0.25EtOAc:C 63.40,H 6.12,N 14.79;found:C 63.72,H 6.22,N 14.58.YMSA-0850:mp 165-170℃.IR(ATR):ν＝2969,1605,1577,1530,1499,1459,1413,1386,1366,1307,1212,1191,1164,1129,1085,1020,1036,963,920,867,813,761,722,653,617,569,526,506,458,424,413cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝9.18(s,1H),8.32(s,1H),7.97(d,J＝8.4Hz,1H),7.89(d,J＝7.5Hz,1H),7.81-7.76(m,1H),7.55-7.50(m,1H),7.15(s,1H),3.70(s,2H),2.68(q,J＝7.2Hz,4H),1.13(t,J＝7.2Hz,6H)ppm.13C NMR(75MHz,CDCl3/TMS):δ＝157.6,155.8,152.6,149.1,138.3,133.1,130.5,127.9,126.6,121.4,119.5,116.1,114.6,109.6,57.0,46.1,11.0ppm.HRMS(ESI+):calcd for[M+H]+,C19H22N4O:357.1477;found 357.1477.Anal.Calcd(％)for C19H21N4O+0.25H2O:C 63.15,H 6.00,N 15.50;found:C 63.05,H 5.83,N 15.64.
EXAMPLE 24 Synthesis of YMSA-0650
[ Chemical formula 24]
To a solution of compound 2 (57 mg,0.20 mmol) dissolved in 3mL of ethanol was added lead chloride dihydrate (0.46 g,2.05 mmol) and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline 4 (72.8 mg,0.4 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 4.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and isolated as a yellow solid YMSA-0650(74mg,91％).mp 70-75℃.IR(ATR):ν＝3263,3056,2975,2826,1616,1604,1567,1535,1457,1441,1409,1386,1349,1322,1300,1255,1223,1195,1169,1155,1120,1112,1087,1066,1054,1026,998,978,945,911,894,875,832,818,798,786,765,677,632,579,561,524,499,474,466,445,433,423cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.71(s,1H),7.91-7.76(m,3H),7.57-7.51(m,1H),7.38-7.30(m,3H),6.85(d,J＝8.4Hz,1H),3.82(s,2H),2.63(q,J＝6.9Hz,4H),1.13(t,J＝7.2Hz,6H)ppm.13C NMR(75MHz,CDCl3/TMS):δ＝158.0,156.0,155.2,149.9,132.7,129.1,128.8,126.4,123.5(2C),122.5,120.5,116.5,115.0,56.9,46.3(2C),11.2(2C)ppm.HRMS(ESI+):calcd for[M+2H]+,C19H24N4O:162.0970;found 162.0970.Anal.Calcd(％)for C19H22N4O+0.1H2O:C 70.39,H 6.90,N 17.28;found:C 70.35,H 6.78,N 17.25.
EXAMPLE 25 Synthesis of YMSA-0828
[ Chemical formula 25]
To a solution of compound 63 (0.10 g,0.37 mmol) dissolved in 4mL of ethanol was added lead chloride dihydrate (0.25 g,1.1 mmol) and stirred under reflux for 3 hours. After cooling to room temperature, 4-chloro-7-methoxyquinazoline 71 (72 mg,0.37 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 12 hours. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate: methanol=30:1) and isolated as a yellow solid YMSA-0828(32mg,21％).mp 163-165℃.IR(ATR):ν＝3371,2974,2921,1621,1604,1579,1533,1497,1469,1452,1416,1386,1372,1340,1305,1243,1227,1193,1172,1126,1068,1024,994,952,929,909,893,875,846,831,796,779,753,722,712,678,660,590,542,517,422,413cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.66(s,1H),7.72(d,J＝9.3Hz,1H),7.52(d J＝2.4,1H),7.26-7.23(m,2H),7.16-7.12(m,2H),3.95(s,3H),3.84(s,2H),3.20-3.11(m,1H),2.60(q,J＝6.9,2H),1.19-1.11(m,9H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝163.3,157.7,155.7,152.3,152.2,129.3,123.7,123.3,122.2,121.9,120.7,118.7,109.3,107.4,55.8,53.0,49.6,43.3,29.8,17.4,13.1ppm.HRMS(FAB+):calcd for[M+H]+,C21H26ClN4O2:401.1744;found 401.1741.Anal.Calcd(％)for C21H25ClN4O2·0.55H2O:C,61.40;H,6.40;N,13.64.found:C,61.50;H,6.31;N,13.35.
Example 26 Synthesis of YMSA-0628
[ Chemical formula 26]
2- ((Benzyl (methyl) amino) methyl) -4-nitrophenol (72)
To a solution of 1 (346.9 mg,2.49 mmol) in 25mL of ethanol was added N-methylbenzylamine (1300. Mu.L, 10.0 mmol) and 37% aqueous formaldehyde (1020. Mu.L, 12.5 mmol), and the mixture was stirred under reflux for 46 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. Chloroform was added to the obtained residue, and back extraction was performed with 1N aqueous hydrochloric acid. Saturated aqueous sodium hydrogencarbonate was added to the aqueous phase, and after neutralization to pH 8, extraction was performed with chloroform. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate (+1% acoh) =4:1 to 1:3), and compound 72 (205.6 mg, 30%) was isolated as a pale yellow solid. mp 80-81 ℃.
2- ((Benzyl (methyl) amino) methyl) -6-iodo-4-nitrophenol (73)
To a solution of compound 72 (105.9 mg,0.38 mmol) dissolved in 1.9mL of acetonitrile was added N-iodosuccinimide (98.3 mg,0.43 mmol), and the mixture was stirred at 0℃for 1.5 hours. After the reaction solution was diluted with methylene chloride, the organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine, dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=2:1), and compound 73 (117.4 mg, 76%) was isolated as a yellow solid. mp 39-40 ℃.
YMSA-0628
Obtained as a pale yellow powdery solid by the same method as in the synthesis of YMSA-0828 YMSA-0628(84.6mg,76％).mp 76-77℃.IR(ATR):ν＝2847,1618,1571,1527,1497,1453,1417,1391,1356,1315,1239,1118,1073,1016,984,914,850,818,743,698,679,613,566,494,451,465,433,411m-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.73(s,1H),7.93-7.88(m,2H),7.80(t,J＝7.5Hz,2H),7.56(t,J＝6.9Hz,1H),7.48(s,1H),7.37-7.22(m,5H),3.78(s,2H),3.67(s,2H),2.28(s,3H)ppm.13C NMR(100MHz,DMSO-d6/TMS):δ＝158.8,155.7,154.5,150.6,137.8,134.0,132.8,132.7,130.4,129.7,128.9,128.8,127.3,124.9,123.9,123.0,116.1,85.0,61.3,60.6,41.5ppm.HRMS(FAB+):calcd for[M+H]+,C23H22N4OI:497.0838;found 497.0838.Anal.Calcd(％)for C23H21IN4O·0.1CHCl3:C,54.59;H,4.18;N,11.02.found:C,54.47;H,4.33;N 11.05.
EXAMPLE 27 Synthesis of YMSA-0908
[ Chemical formula 27]
2- ((Dipropylamino) methyl) -4-nitrophenol (75)
Dipropylamine (168. Mu.L, 1.2 mmol) and Et 3 N (167. Mu.L, 1.2 mmol) were added to a solution of 2-hydroxy-5-nitrobenzyl bromide (39) (232 mg,1.0 mmol) in THF (4 mL) and the reaction solution heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure, saturated aqueous NaHCO 3 was added and extracted with AcOEt. The combined organic phases were washed with saturated brine, dried over Na 2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/acoet=1/1) to obtain compound 75 (249.9 mg, 99%) as a yellow oily substance.
2-Chloro-6- ((dipropylamino) methyl) -4-nitrophenol (76)
N-chlorosuccinimide (152.2 mg,1.14 mmol) was added to a solution of compound 75 (238.5 mg,0.95 mmol) in MeCN (5 mL) and the reaction solution was stirred at room temperature for 27.5 hours. The reaction solution was concentrated under reduced pressure, 10% aqueous na 2S2O3 was added, and extraction was performed with AcOEt (30 ml×4). The combined organic phases were washed with saturated brine, dried over Na 2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/AcOEt/=1/3) to give compound 76 (101.1 mg, 37%) as a yellow solid. mp 124 ℃.
YMSA-0908
Obtained as a yellow solid by the same method as the synthesis of YMSA-0464 YMSA-0908(120.4mg,89％).mp 144-145℃.IR(ATR):ν＝2963,1706,1667,1618,1574,1536,1499,1468,1406,1357,1321,1229,1126,1075,1026,968,922,868,842,820,796,764,684,592,572,547,468,423,411cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.73(s,1H),7.90(d,J＝8.1Hz,2H),7.79(t,J＝7.5Hz,1H),7.58-7.51(m,3H),3.77(s,2H),2.54-2.48(m,4H),1.64-1.52(m,4H),0.90(t,J＝7.4Hz,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝162.3,158.0,154.7,151.5,149.4,134.4,132.8,129.2,128.0,127.3,127.0,126.3,123.6,123.0,122.6,121.7,120.3,115.0,57.8,55.0,19.0ppm.HRMS(ESI+):calcd for[M+H]+,C21H26ClN4O:385.1790;found 385.1780.Anal.Calcd(％)for C21H26ClN4O:C 65.53,H 6.55,N 14.56;found C 65.49,H 6.14,N 14.63.
EXAMPLE 28 Synthesis of YMSA-0868
[ Chemical formula 28]
2- ((Ethyl (phenyl) amino) methyl) -4-nitrophenol (81)
To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g,1.0 mmol) in 4mL of tetrahydrofuran was added N-ethylaniline (151.5. Mu.L, 1.2 mmol) and triethylamine (306.1. Mu.L, 2.2 mmol), and the mixture was stirred under reflux for 20.5 hours. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=4:1), and compound 81 (255 mg, 97%) was isolated as a yellow solid. mp 113-117 ℃.
2- (((4-Chlorophenyl) (ethyl) amino) methyl) -4-nitrophenol (82)
To a solution of compound 81 (265 mg,0.97 mmol) dissolved in 5mL of acetonitrile was added N-chlorosuccinimide (155.9 mg,1.17 mmol) and the mixture was stirred at room temperature for 72 hours. The solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1), and compound 82 (127.7 mg, 43%) was isolated as a yellow solid. mp 105-114 ℃.
YMSA-0868
To a solution of compound 82 (61.1 mg,0.2 mmol) dissolved in 2mL of ethanol was added lead chloride dihydrate (179.9 mg,0.8 mmol) and stirred under reflux for 2.5 hours. After cooling to room temperature, 4-chloroquinazoline 4 (65.7 mg,0.4 mmol) was added to the reaction solution, and the mixture was stirred again under reflux for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 2N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) and isolated as a white solid YMSA-0868(27.7mg,34％).mp 215℃(dec.).IR(ATR):ν＝2967,1616,1596,1578,1499,1443,1402,1384 1351,1304,1290,1272,1242,1208,1187,1147,1131,1099,1071,985,959,911,863,817,786,761,745,709,683,652,592,562,545,511,462,423,416cm-1.1HNMR(300MHz,CDCl3/TMS):δ＝8.72(s,1H),7.91(d,J＝8.1Hz,1H),7.85-7.78(m,2H),7.55(t,J＝7.65Hz,1H),7.47(s,1H),7.40(d,J＝8.4Hz,1H),7.27-7.24(m,2H),7.03(d,J＝9.0Hz,2H),6.89(d,J＝8.4Hz,1H),4.38(s,2H),3.34-3.27(m,2H),1.07(t,J＝6.9Hz,3H)ppm.HRMS(FAB+):calcd for[M+H]+,C23H21ClN4O:404.1405;found 404.1404.
EXAMPLE 29 Synthesis of YMSA-0884
[ Chemical formula 29]
2- ((Isopropyl (phenyl) amino) methyl) -4-nitrophenol (83)
To a solution of 2-hydroxy-5-nitrobenzyl bromide 39 (0.23 g,1.0 mmol) in 4mL of tetrahydrofuran was added N-isopropylaniline (172.6. Mu.L, 1.2 mmol) and triethylamine (306.1. Mu.L, 2.2 mmol), and the mixture was stirred under reflux for 20.5 hours. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=4:1), and compound 83 (233.2 mg, 81%) was isolated as a yellow solid. mp 129-133 ℃.
2- (((4-Chlorophenyl) (isopropyl) amino) methyl) -4-nitrophenol (84)
To a solution of compound 83 (233.2 mg,0.81 mmol) dissolved in 5mL of acetonitrile was added N-chlorosuccinimide (130.4 mg,0.98 mmol), and the mixture was stirred at room temperature for 72 hours. The solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1), and compound 84 (224.3 mg, 85%) was isolated as a yellow solid. mp 83-85 ℃.
YMSA-0884
To a solution of compound 84 (102 mg,0.32 mmol) dissolved in 2mL of ethanol was added lead chloride dihydrate (287.5 mg,1.27 mmol) and stirred under reflux for 2.5 hours. After cooling to room temperature, 4-chloroquinazoline 4 (104.9 mg,0.64 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 2N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) and isolated as a yellow solid YMSA-0884(72.6mg,55％).mp 94-105℃.IR(ATR):ν＝2970,1619,1576,1532,1493,1443,1391,1358,1319,1295,1252,1187,1126,1071,1040,987,959,919,808,746,695,681,666,595,546,513,466cm-1.1HNMR(300MHz,CDCl3/TMS):δ＝8.72(s,1H),7.90(d,J＝7.8Hz,1H),7.83-7.77(m,2H),7.54(t,J＝7.5Hz,1H),7.47(d,J＝3.0Hz,1H),7.31-7.25(m,2H),7.15(d,J＝7.8Hz,2H),7.09-7.05(m,1H),6.80(d,J＝9.0Hz,1H),4.42(s,2H),3.70(hep,J＝6.6,1H),1.19(d,J＝6.6Hz,6H)ppm.13CNMR(100MHz,CDCl3/TMS):δ＝158.0,155.1,149.7,147.1,133.0,129.5,129.0,128.8,126.6,124.1,123.7,123.5,123.4,123.0,120.5,116.7,115.0,54.4,51.0,19.1ppm.HRMS(FAB+):calcd for[M+H]+,C24H23ClN4O:419.1636;found 419.1639.Anal.Calcd(％)for C24H23ClN4O:C,68.81;H,5.53;N,13.37.found:C,67.07;H,5.66;N,13.14.
EXAMPLE 30 Synthesis of YMSA-0909
[ Chemical formula 30]
2-Chloro-6- (((4-chlorophenyl) (ethyl) amino) methyl) -4-nitrophenol (85)
To a solution of compound 65 (205.0 mg,1.00 mmol) dissolved in 4mL of chloroform was added phosphorus tribromide (100. Mu.L, 1.05 mmol), and the mixture was stirred at room temperature for 23 hours. After quenching the reaction mixture with water, the mixture was extracted 3 times with chloroform. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture (214.9 mg) was dissolved in tetrahydrofuran (3.2 mL), N-ethyl-4-chloroaniline (136. Mu.L, 0.978 mmol) and triethylamine (248. Mu.L, 1.78 mmol) were added, and stirred under reflux for 2.5 hours. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=10:1 to 1:1), and compound 85 (153.8 mg, 45%) was isolated as a yellow solid. mp 118-119 ℃.
YMSA-0909
To a solution of compound 85 (68 mg,0.20 mmol) dissolved in 2mL of ethanol was added lead chloride dihydrate (0.18 g,0.80 mmol) and stirred under reflux for 2.5 hours. After cooling to room temperature, 4-chloroquinazoline 4 (72.8 mg,0.4 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 2.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=5:1) and isolated as a pale brown solid YMSA-0909(12mg,14％).mp 185-192℃.IR(ATR):ν＝2969,1741,1621,1595,1574,1534,1500,1474,1428,1406,1364,1307,1289,1266,1221,1168,1129,1074,982,922,865,823,812,786,761,718,701,679,647,623,599,577,557,531,506,467,438,427,414cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.72(s,1H),7.93-7.90(m,1H),7.84-7.78(m,3H),7.61-7.53(m,1H),7.24-7.20(m,3H),6.83(d,J＝8.7Hz,2H),4.45(s,2H),3.34(q,J＝6.9Hz,2H),1.14(t,J＝6.9Hz,3H)ppm.HRMS(FAB):Calcd for[M+H]+,C23H21Cl2N4O:439.1092;found 439.1091.
EXAMPLE 31 Synthesis of YMSA-0651
[ Chemical formula 31]
To a solution of YMSA-0329 (51 mg,0.20 mmol) in 2mL of methanol were added diethylamine (82.7. Mu.L, 0.80 mmol) and paraformaldehyde (30 mg,5.2 mmol) and stirred under reflux for 17 hours. After confirming that the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained mixture was purified by silica gel column chromatography (ethyl acetate: methanol=1:0 to 9:1) and separated as a yellow solid YMSA-0651(18.5mg,27％).mp 163-167℃.IR(ATR):ν＝3264,3058,2974,2829,1619,1568,1538,1492,1475,1446,1406,1394,1354,1331,1318,1288,1271,1242,1212,1194,1167,1150,1120,1088,1055,1028,1003,965,916,867,819,798,766,725,678,614,591,557,530,506,466,434,424,410cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.74(s,1H),7.93(d,J＝8.1Hz,1H),7.84-7.78(m,2H),7.56(t,J＝7.2Hz,1H),7.46-7.41(m,1H),7.11(s,1H),3.86(s,2H),2.67(q,J＝7.2Hz,2H),1.15(t,J＝7.2Hz,9H)ppm.13C NMR(75MHz,CDCl3/TMS):δ＝157.8,154.9,152.3,150.0,149.1,144.0,143.8,132.9,128.8,128.6,126.5,124.1,124.0,120.6,117.8,117.7,115.0,110.7,110.5,56.8,46.4,11.1ppm.HRMS(ESI+):calcd for[M+H]+,C19H22FN4O:341.1772;found 341.1771.Anal.Calcd(％)for C19H21FN4O+0.5MeOH:C 65.71,H 6.50,N 15.72;found:C65.69,H 6.12,N 15.79.
EXAMPLE 32 Synthesis of YMSA-0833
[ Chemical formula 32]
N- (pyridin-4-ylmethyl) propan-2-amine (2)
Compound 1 (469. Mu.L, 5.0 mmol) was dissolved in 5mL of methanol, and isopropylamine (428. Mu.L, 5.0 mmol) was added thereto and stirred at room temperature for 2.5 hours. Sodium borohydride (208 mg,5.5 mmol) was added to the reaction solution, and the mixture was stirred for 13 hours. After completion of the reaction, H 2 O and 3N aqueous sodium hydroxide solution were added, followed by extraction with chloroform. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (chloroform: methanol: triethylamine=10:1:0.1), and the compound was isolated as a colorless liquid 2(329mg,44％).IR(ATR):ν＝3284,2965,2115,1603,1561,1468,1415,1381,1337,1309,1220,1174,1127,1092,1065,994,800,748,663,594,528,477,443,415,407cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.54-8.52(m,2H),7.27-7.26(m,2H),3.81(s,2H),2.84(sept,J＝6.3Hz,1H),1.10(d,J＝6.3Hz,9H)ppm.13CNMR(100MHz,CDCl3/TMS):δ＝150.0,149.7,149.6,123.1,121.2,50.2,48.4,22.9(2C)ppm.HRMS(ESI+):calcd for[M+H]+,C9H15N2:151.1230;found 151.1225.
2- ((Isopropyl (pyridin-4-ylmethyl) amino) methyl) -4-nitrophenol (3)
Compound 2 (329 mg,2.2 mmol) was dissolved in 10mL of tetrahydrofuran, triethylamine (306. Mu.L, 2.2 mmol) was added, and 2-hydroxy-5-nitrobenzyl bromide (425 g,1.83 mmol) was stirred under reflux for 1.5 hours. After completion of the reaction was confirmed, the solvent was distilled off, and the residue was diluted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1→0:1) and the compound was isolated as a yellow solid 3(227mg,43％).IR(ATR):ν＝1621,1589,1524,1477,1416,1397,1374,1343,1287,1273,1224,1180,1158,1132,1090,1073,1045,977,923,911,883,856,835,813,776,762,752,736,713,670,635,614,547,494,447,422cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.52-8.50(m,2H),8.23(brs,1H),8.09-8.06(m,1H),7.69(d,J＝8.1Hz,1H),7.46(t,J＝8.1Hz,1H),7.29(d,J＝6.0Hz,1H),3.66(s,2H),3.59(s,2H),2.90(sept,J＝6.6Hz,1H),1.11(d,J＝6.6Hz,9H)ppm.13CNMR(100MHz,CDCl3/TMS):δ＝162.9,149.5,148.7,139.4,126.0,124.8,124.2,123.5,115.3,52.2,49.8,48.3,17.4ppm.HRMS(ESI+):calcd for[M+H]+,C16H20N3O3:302.1505;found 302.1495.
2-Chloro-6- ((isopropyl (pyridin-4-ylmethyl) amino) methyl) -4-nitrophenol (4)
To a solution of compound 3 (143 mg,0.5 mmol) dissolved in 4.5mL of acetonitrile and 0.2mL of acetic acid was added N-chlorosuccinimide (80 mg,0.6 mmol), and the mixture was stirred at room temperature for 44 hours. The solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) and the compound was isolated as a yellow solid 4(63.1mg,38％).IR(ATR):ν＝3089,2980,1599,1563,1468,1420,1374,1329,1230,1215,1173,1091,1022,991,910,894,876,852,822,811,747,715,666,655,594,546,529,480,412cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.62(d,J＝5.7Hz,2H),8.20(d,J＝3.0Hz,1H),7.87(d,J＝2.7Hz,1H),7.26-7.25(m,1H),3.91(s,2H),3.67(s,2H),3.08(sept,J＝6.6Hz,1H),1.21(d,J＝6.6Hz,9H)ppm.13CNMR(100MHz,CDCl3/TMS):δ＝171.8,166.5,149.9,143.0,124.8,124.5,120.9,120.7,52.1,51.9,51.8,16.4ppm.HRMS(ESI+):calcd for[M+H]+,C16H19ClN3O3:336.1115;found 336.1109.
YMSA-0833
To a solution of compound 4 (49.5 mg,0.15 mmol) dissolved in 4mL of ethanol was added tin chloride dihydrate (133 mg,0.59 mmol) and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (48.5 mg,0.29 mmol) was added to the reaction mixture, and the mixture was stirred again under reflux for 1.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to isolate the compound as a pale yellow solid YMSA-0833(30mg,47％).M.p.98-101℃.IR(ATR):ν＝2967,1620,1601,1574,1533,1477,1393,1358,1318,1236,1157,1127,1073,987,919,869,765,721,680,623,580,556,534,506,467,421,413ppm.1H NMR(300MHz,CDCl3/TMS):δ＝8.73(s,1H),8.59(d,J＝6.0Hz,2H),7.93(d,J＝8.4Hz,1H),7.85-7.82(m,2H),7.61-7.53(m,2H),7.53(d,J＝2.7Hz,1H),7.41(d,J＝2.4Hz,1H),3.86(s,2H),3.66(s,2H),3.09(sept,J＝6.6Hz,1H),1.18(d,J＝6.6Hz,9H)ppm.13CNMR(100MHz,CDCl3/TMS):δ＝157.7,154.5,149.8,149.5,149.2,147.4,132.9,131.0,127.8,126.2,124.3,124.0,122.8,122.7,122.3,118.8,115.0,51.8,51.4,49.3,17.0ppm.HRMS(ESI+):calcd for[M+H]+,C24H25ClN5O:434.1748;found 434.1742.
EXAMPLE 33 Synthesis of YMSA-0866
[ Chemical formula 33]
N-ethyl-2-methylpropan-1-amine (6)
Compound 5 (0.20 g,0.99 mmol) was dissolved in 1mL of dioxane, and a 4N dioxane solution (3.0 mL,12 mmol) of hydrochloric acid was added and stirred at room temperature for 1 hour. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure. The resulting solid was washed with diethyl ether and compound 6 (84 mg, 62%) was isolated as a colorless solid.
M.p.192-194℃.IR(ATR):ν＝2963,2808,2748,2690,2528,2446,2393,2323,1601,1512,1480,1468,1446,1348,1327,1251,1181,1157,1100,1039,1019,973,960,943,923,865,825,802,498,442,419cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝9.40(s,1H),3.13-3.02(m,2H),2.79-2.73(m,2H),2.33-2.19(m,1H),1.50(t,J＝7.2Hz,3H),1.12(d,J＝6.6,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝54.4,43.4,25.9,20.8,11.0ppm.HRMS(ESI( Positive ion mode) calcd for [ m+h ] +,C6H16 N:102.1277; found 102.1278.
2- ((Ethyl (isobutyl) amino) methyl) -4-nitrophenol (7)
To a solution of 2-hydroxy-5-nitrobenzyl bromide (71 mg,0.31 mmol) dissolved in 1mL of tetrahydrofuran was added compound 6 (41 mg,0.30 mmol) and triethylamine (80. Mu.L, 0.60 mmol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. Purifying the resulting mixture by silica gel column chromatography (hexane: ethyl acetate=4:1), separating compound 7(68.6mg,91％).M.p.78.5-79.8℃.IR(ATR):ν＝2956,2873,1591,1553,1509,1478,1435,1402,1380,1340,1305,1264,1204,1142,1114,1088,1053,982,966,897,881,870,822,795,761,746,714,535,523,481,465cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.09(dd,J＝3.0,2.4Hz,1H),7.93(d,J＝3.0,1H),6.82(d,J＝9.0,1H),3.82(s,2H),2.62(q,J＝7.2,2H),2.34(d,J＝7.5,2H),1.99-1.86(m,J＝6.6,1H),1.11(t,J＝6.9,3H),0.96(d,J＝6.6,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝165.2,139.7,125.3,124.5,121.9,116.3,61.7,57.6,46.7,25.7,20.8,10.0ppm.HRMS(ESI( positive ion mode as a yellow solid)) calcd for [ m+h ] +,C13H21N2O3: 253.1547; found 253.1547.
2-Chloro-6- ((ethyl (isobutyl) amino) methyl) -4-nitrophenol (8)
To a solution of compound 7 (40 mg,0.16 mmol) dissolved in acetonitrile 0.9mL and acetic acid 0.1mL was added N-chlorosuccinimide (25 mg,0.19 mmol), and the mixture was stirred at room temperature for 21.5 hours. The solvent was distilled off under reduced pressure, then a saturated aqueous sodium hydrogencarbonate solution was added, and extraction was performed with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=2:1 to 1:5) and compound 8(32.8mg,71％).M.p.99.8-102.1℃.IR(ATR):ν＝3508,3395,3093,2924,1603,1583,1519,1462,1422,1338,1255,1208,1169,1085,1051,979,940,899,865,799,752,742,710,639,557,542,521,472,417cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.23(d,J＝2.4Hz 1H),7.84(d,J＝2.4,1H),3.92(s,2H),2.73(q,J＝7.2,2H),2.47(d,J＝7.5,2H),2.04-1.94(m,1H),1.18(t,J＝7.2,3H),1.02(d,J＝6.6,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝163.6,137.7,125.7,122.9,121.8,120.5,61.4,57.7,46.7,25.5,20.8,9.5ppm.HRMS(ESI( was isolated as a yellow solid in positive ion mode )):calcd for[M+H]+,C13H20 35ClN2O3:287.1157;found 287.1157.
YMSA-0866(TY-1)
To a solution of compound 8 (19 mg,0.06 mmol) dissolved in 1mL of ethanol was added tin chloride dihydrate (45 mg,0.21 mmol) and stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (12 mg,0.07 mmol) was added to the reaction solution, and the mixture was stirred again under reflux for 2 hours. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1), separating compound YMSA-0866(21mg,84％).M.p.137.3-140.2℃.IR(ATR):ν＝2959,1620,1572,1532,1499,1467,1389,1356,1317,1287,1237,1191,1163,1125,1074,1043,990,958,917,868,820,763,726,679,581,544,466,433,408cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.74(s,1H),7.93-7.90(m,1H),7.83-7.78(m,2H),7.60-7.53(m,2H),7.30(d,J＝2.7Hz,1H),7.22(s,1H),3.81(s,2H),2.62(q,J＝7.2,2H),2.34(d,J＝7.5,2H),1.93(m,1H),1.11(t,J＝7.2,3H),0.98(d,J＝6.6,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝157.7,155.0,151.6,150.0,132.9,129.3,129.0,126.6,123.4,121.6,120.7,120.1,114.9,62.0,58.1,46.8,25.8,21.0,10.2ppm.HRMS(ESI( positive ion mode as a yellow solid)) calcd for [ m+h ] +,C21H26 35ClN4 O385.1790; found 385.1788.
EXAMPLE 34 Synthesis of YMSA-0911
[ Chemical formula 34]
N- (3-chloro-2-methoxy-5-nitrobenzyl) -N-isopropyl-2-amine (10)
To a solution of compound 9 (57.3 mg,0.2 mmol) dissolved in 4mL of acetonitrile was added potassium carbonate (138 mg,1 mmol) and methyl iodide (62. Mu.L, 1 mmol), and the mixture was stirred under reflux for 3 hours. The solvent was distilled off under reduced pressure, followed by addition of H 2 O and extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=9:1), and the compound was isolated as a colorless oily substance 10(49.2mg,82％).1H NMR(300MHz,CDCl3/TMS):δ＝8.47(d,J＝2.4Hz,1H),8.12(d,J＝2.1Hz,1H),3.93(s,3H),3.72(s,2H),3.05(sept,J＝6.6Hz,1H),1.04(d,J＝6.6Hz,12H)ppm.HRMS(ESI+):calcd for[M+H]+,C14H22ClN2O3:301.1319;found:301.1313.
YMSA-0911(TTn-146)
To a solution of compound 10 (28 mg,0.09 mmol) dissolved in 1.5mL of ethanol was added tin chloride dihydrate (81 mg,0.36 mmol), and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (30 mg,0.18 mmol) was added to the reaction solution, and stirred again under reflux for 3 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate) and the compound was isolated as a yellow solid YMSA-0911(95mg,quant.).1H NMR(300MHz,CDCl3/TMS):δ＝8.80(s,1H),7.95-7.89(m,3H),7.85-7.79(m,1H),7.67(d,J＝3.0Hz,1H),7.61-7.56(m,1H),7.41(s,1H),3.86(s,3H),3.76-3.73(m,2H),3.12-3.01(m,1H),1.06(d,J＝6.6Hz,12H)ppm.HRMS(ESI+):calcd for[M+H]+,C22H28ClN4O:399.1952;found 399.1947.
Example 35 Synthesis of YMSA-0944
[ Chemical formula 35]
3-Chloro-N-ethyl-4-fluoroaniline (12)
To a solution of compound 11 (500.0 mg,3.4 mmol) dissolved in 6mL of methanol were added sodium bicarbonate (1154.1 mg,13.7 mmol) and acetaldehyde (776 uL,13.7 mmol), and the mixture was stirred under reflux for 3 hours. After cooling to room temperature, the solvent and acetaldehyde were distilled off under reduced pressure. To the resulting residue was added 15mL of methanol and sodium borohydride (390.4 mg,10.3 mmol), and the mixture was stirred at room temperature for 1 hour. After confirming that the reaction was completed, the reaction solution was slowly added to a mixture of ethyl acetate and 2M hydrochloric acid, the organic phase was extracted with 2N hydrochloric acid, and the obtained aqueous phase was neutralized to pH 11 with 5N aqueous sodium hydroxide solution. After the neutralized aqueous phase was extracted 3 times with chloroform, it was dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. Purifying the obtained mixture by silica gel column chromatography (hexane) to separate the compound as colorless oil 12(336.7mg,56％).IR(ATR):ν＝3420,2972,2876,1612,1503,1452,1396,1323,1260,1219,1148,1099,1063,1046,946,923,840,799,781,742,702,689,584,518,443,418cm- 1.1H NMR(300MHz,CDCl3/TMS):δ＝6.93(t,J＝9.0Hz,1H),6.58(dd,J＝6.2,2.9Hz,1H),6.41(td,J＝9.0,3.3Hz,1H),3.48(brs,1H),3.09(q,J＝6.9Hz,2H),1.25(t,J＝6.9Hz,3H)ppm;13C NMR(100MHz,CDCl3/TMS):δ＝150.8(d,JC,F＝235.7Hz),145.5,121.0(d,JC,F＝18.2Hz),116.8(d,JC,F＝22.0Hz),113.5,112.1(d,JC,F＝5.8Hz),38.9,14.7ppm;HRMS(ESI positive):calcd for[M+H]+,C8H10 35ClFN:174.0480;found 178.0480.
2-Chloro-6- (((3-chloro-4-fluorophenyl) (ethyl) amino) methyl) -4-nitrophenol (14)
To a solution of compound 13 (61.1 mg,0.3 mmol) dissolved in chloroform 1mL was added PBr 3 (85.5. Mu.L, 0.90 mmol), and the mixture was stirred at room temperature for 16 hours. After completion of the reaction was confirmed, the reaction solution was diluted with chloroform, and the organic phase was washed with water and saturated brine, dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture (264.6 mg) was dissolved in 1mL of dichloroethane, and a solution of triethylamine (125. Mu.L, 0.90 mmol) and 12 (78.1 mg,0.45 mmol) in methylene chloride (2 mL) was added thereto and stirred at room temperature for 2 hours. After confirming that the reaction was completed, the reaction solution was diluted with chloroform, and the organic phase was washed with 1N hydrochloric acid, a saturated sodium bicarbonate aqueous solution and a saturated brine, and then dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=5:1) and the compound was isolated as a yellow solid 14(94.3mg,0.26mmol,88％for steps).M.p.101-102℃.IR(ATR):ν＝3403,3102,2979,2936,1610,1584,1504,1466,1440,1398,1376,1325,1284,1271,1223,1193,1178,1130,1068,1049,981,941,922,896,868,842,794,742,722,681,560,524,490,443,413cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.23(d,J＝3.0Hz,1H),7.91(d,J＝2.7Hz,1H),7.07-7.15(m,2H),6.92-6.97(m,1H),4.40(s,2H),3.23(q,J＝4.2Hz,2H),1.11(t,J＝4.2Hz,2H)ppm;13C NMR(100MHz,CDCl3/TMS):δ＝158.6,154.8(d,JC,F＝244.9Hz),153.6,144.1(d,JC,F＝2.9Hz),140.4,125.2,123.3,122.6(d,J＝9.6Hz),122.0,121.8,121.5,120.4(d,JC,F＝6.7Hz),117.3(d,JC,F＝21.1Hz),55.8,49.1,11.3ppm;HRMS(ESI positive):calcd for[M+H]+,C15H14 35Cl2FN2O3:359.0360;found 359.0359.
YMSA-0944
To a solution of compound 14 (78.0 mg,0.22 mmol) dissolved in 2mL of ethanol was added tin chloride dihydrate (147.0 mg,0.65 mmol) and stirred under reflux for 30 min. After cooling to room temperature, 4-chloroquinazoline (46.4 mg,0.28 mmol) was added to the reaction solution, and stirred again under reflux for 4 hours. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=10:1 to 2:1,1% triethylamine) and TLC (hexane: ethyl acetate=3:1, 1% triethylamine) was used for separation to isolate the compound as a pale yellow solid YMSA-0911(7.1mg,7％).1H NMR(300MHz,CDCl3/TMS):δ＝8.72(s,1H),7.78-7.93(m,4H),7.55(t,J＝6.9Hz,1H),7.23(t,J＝2.4Hz,1H),7.02(t,J＝9.0Hz,1H),6.95(dd,J＝6.2,2.9Hz,1H),4.41(s,2H),3.33(q,J＝7.2Hz,2H),1.15(t,J＝7.2Hz,)ppm;HRMS(ESI positive):calcd for[M+H]+,C23H20 35Cl2FN4O:457.0993;found 457.0992.
EXAMPLE 36 Synthesis of YMSA-0958
[ Chemical formula 36]
2- (((3R, 5S) -3, 5-dimethylpiperidin-1-yl) methyl) -4-nitrophenol (16)
To a solution of 2-hydroxy-5-nitrobenzyl bromide (153 mg,0.66 mmol) dissolved in 2mL of tetrahydrofuran was added compound 15 (89.5 mg,0.79 mmol) and triethylamine (202. Mu.L, 1.5 mmol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1), and the compound was isolated as a yellow oily substance 16(173mg,99％).1H NMR(300MHz,CDCl3/TMS):δ＝8.09(dd,J＝2.7,9.0Hz,1H),7.92(d,J＝2.7Hz,1H),6,83(d,J＝8.7Hz,1H),3.77(s,2H),2.90(d,J＝9.0Hz,2H),1.81-1.66(m,5H),0.89(d,J＝6.0Hz,6H),0.69-0.58(m,1H)ppm.HRMS(ESI+):calcd for[M+H]+,C14H21N2O3:265.1552;found 265.1544.
2-Chloro-6- (((3R, 5S) -3, 5-dimethylpiperidin-1-yl) methyl) -4-nitrophenol (17)
To a solution of compound 16 (154 mg,0.58 mmol) dissolved in 3mL of acetonitrile was added N-chlorosuccinimide (93 mg,0.70 mmol), and the mixture was stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and the compound was isolated as a yellow solid 17(34mg,19％).1H NMR(300MHz,CDCl3/TMS):δ＝8.23(d,J＝3.0Hz,1H),7.83(d,J＝3.0Hz,1H),3.85(s,2H),2.98(d,J＝6.6Hz,2H),1.85-1.82(m,5H),0.91(d,J＝5.7Hz,6H),0.67-0.66(m,1H)ppm.
YMSA-0958
To a solution of compound 17 (29.8 mg,0.10 mmol) dissolved in 2mL of ethanol was added tin chloride dihydrate (90.4 mg,0.40 mmol) and stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (33 mg,0.20 mmol) was added to the reaction solution, and stirred again under reflux for 2.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to isolate the compound as a pale yellow solid YMSA-0958(34.6mg,87％).M.p.48-49℃.IR(ATR):ν＝2955,2911,1619,1574,1537,1498,1466,1405,1357,1319,1228,1125,1967,999,962,921,899,868,819,796,777,761,732,684,654,594,547,519,503,467,446,417ppm.1H NMR(300MHz,CDCl3/TMS):δ＝8.74(s,1H),7.92(d,J＝8.1Hz,1H),7.84-7.78(m,2H),7.59-7.53(m,2H),7.28-7.23(m,1H),3.74(s,2H),2.95(d,J＝9.3Hz,2H),1.79-1.62(m,5H),0.88(d,J＝6.3Hz,6H),0.67-0.59(m,1H)ppm.13CNMR(100MHz,CDCl3/TMS):δ＝165.2,125.2,124.6,121.3,116.4,61.0,60.3,41.4,31.1,19.2ppm.HRMS(ESI+):calcd for[M+H]+,C22H26ClN4O:397.1795;found 397.1789.
EXAMPLE 37 Synthesis of YMSA-0968
[ Chemical formula 37]
2-Amino-3-chloro-5-nitrobenzoic acid ethyl ester (19)
To a solution of compound 18 (538 mg,2.54 mmol) dissolved in 9mL of acetonitrile and 1mL of acetic acid was added N-chlorosuccinimide (340 mg,2.54 mmol), and the mixture was stirred at room temperature for 8 hours. N-chlorosuccinimide (340 mg,2.54 mmol) was further added to the reaction solution, and stirred at room temperature for 13 hours. The solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=5:1) and the compound was isolated as a yellow solid 19(604mg,97％).M.p.145-146℃.IR(ATR):ν＝3470,3339,3103,2988,1851,1804,1695,1603,1585,1557,1505,1467,1429,1374,1314,1251,1220,1141,1115,1081,1025,938,929,906,874,823,793,742,710,662,600,507,461cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.79(d,J＝2.4Hz,1H),8.33(d,J＝2.7Hz,1H),4.41(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝166.4,151.0,136.2,128.5,126.9,120.0,110.2,61.8,14.2ppm.HRMS(ESI+):calcd for[M+H]+,C9H10ClN2O4:245.0329;found 245.0328.
2-Amino-3-chloro-5-nitrophenylmethanol (20)
To a solution of compound 19 (490 mg,2 mmol) dissolved in 2mL of tetrahydrofuran were added LiBH 4 (2M solution, 1.5mL,3 mmol) and methanol (125. Mu.L, 3 mmol) in THF, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, methanol was added until no foaming occurred. After the solvent was distilled off, ethyl acetate was added to the obtained residue, and the organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine, and then dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to isolate the compound as a colorless solid 20(305mg,76％).M.p.158-159℃.IR(ATR):ν＝3521,3417,3336,3233,3099,2867,1651,1597,1577,1484,1457,1439,1395,1297,1220,1188,1105,1054,979,947,896,855,821,743,734,628,543,480cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.06(s,1H),6.56(s,1H),5.51(s,1H),4.46(d,J＝4.5Hz,2H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝147.9,135.7,126.3,123.8,121.5,115.9,59.7ppm.HRMS(ESI+):calcd for[M+H]+,C7H8ClN2O3:203.0223;found 203.0224.
2-Chloro-6- ((ethyl (isopropyl) amino) methyl) -4-nitroaniline (21)
To a solution of compound 20 (101 mg,0.5 mmol) dissolved in 5mL of dichloromethane was added triethylamine (416 μl,3 mmol) and methanesulfonyl chloride (155 μl,2 mmol), and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, 1N hydrochloric acid and methylene chloride were added. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solid was removed by filtration. The solvent was distilled off under reduced pressure to give methanesulfonate (118 mg, 85%). The resulting methanesulfonate was dissolved in acetonitrile (4 mL), diisopropylamine (295. Mu.L, 2.1 mmol) was added, and stirred at room temperature for 1 hour. After the solvent was distilled off, purification was performed by means of silica gel column chromatography (hexane: ethyl acetate=4:1), and compound 21 (68 mg, 56%) was isolated as a colorless solid.
1H NMR(300MHz,CDCl3/TMS):δ＝8.15(d,J＝2.7Hz,1H),7.90(d,J＝2.1Hz,1H),6.47(br,1H),3.81(s,2H),3.08-2.99(m,2H),1.07(m,12H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝150.1,137.3,124.5,123.0,49.2,47.3,29.7,20.0ppm.HRMS(ESI+):calcd for[M+H]+,C13H21ClN3O2:286.1322;found 286.1319.
N- (2-chloro-6- ((ethyl (isopropyl) amino) methyl) -4-nitrophenyl) methanesulfonamide (22)
To a solution of compound 21 (28.6 mg,0.1 mmol) dissolved in 0.5mL of dimethylformamide was added sodium hydride (4.4 mg,0.1 mmol) and stirred for 30 minutes. Methanesulfonyl chloride (7.7. Mu.L, 0.1 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 34 hours. After completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate were added. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solid was removed by filtration. After the solvent was distilled off, purification was performed by silica gel column chromatography (hexane: ethyl acetate=10:1), and the compound was isolated as a colorless solid 22(14mg,39％).1H NMR(300MHz,CDCl3/TMS):δ＝8.27(d,J＝2.4Hz,1H),8.02(d,J＝2.4Hz,1H),4.06(s,2H),3.36(s,3H),3.27-3.14(m,3H),1.15(d,J＝6.6Hz,12H).
YMSA-0968
To a solution of compound 22 (13.5 mg,0.037 mmol) dissolved in 1mL of ethanol was added tin chloride dihydrate (33.6 mg,0.15 mmol) and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (14.4 mg,0.087 mmol) was added to the reaction solution, and stirred again under reflux for 1 hour. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to isolate the compound as a pale yellow solid YMSA-0968(6.1mg,36％).1H NMR(300MHz,CDCl3/TMS):δ＝8.80(s,1H),8.01-7.93(m,3H),7.86-7.81(m,1H),7.63-7.58(m,3H),3.84(s,2H),3.36(m,3H),3.12-3.03(m,2H),1.05(d,J＝6.6Hz,12H)ppm.13CNMR(100MHz,CDCl3/TMS):δ＝157.8,155.0,151.7,149.9,132.9,129.3,128.9,126.6,123.6,122.7,121.6,120.7,120.3,61.6,60.5,41.5,31.1,19.3ppm.
EXAMPLE 38 Synthesis of YMSA-0973
[ Chemical formula 38]
YMSA-0974
To a solution of compound YMSA-0785 (35.0 mg,0.091 mmol) dissolved in dimethylformamide 0.5mL was added sodium hydride (55% in paraffin oil, 4.4mg,0.10 mmol) and stirred at room temperature for 15 minutes. Thereafter, 2 in DMF (0.5 mL) was added and stirred at room temperature for 6 hours. Thereafter, stirring was carried out at 80℃for 12 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The resulting residue was diluted with chloroform, and the organic phase was washed with water and saturated brine, dried over sodium sulfate, and the solid was removed by filtration. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2:1 to 1:1,1% et 3 N) to give a mixture (18 mg) containing the deprotected substance. The resulting mixture (18 mg) was dissolved in mL of methanol, and sodium methoxide was added thereto to react at room temperature for 1 hour. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography (chloroform/methanol=50:1 to 10:1,1% et 3 N) to obtain compound YMSA-0974 (8.4 mg, two-step yield 17％).1H NMR(400MHz,CD3OD/TMS):δ＝8.40(d,J＝8.8Hz,1H),8.01(d,J＝2.4Hz,1H),7.85-7.87(m,1H),7.80(d,J＝8.4Hz,1H),7.74(d,J＝2.4Hz,1H),7.64-7.66(m,1H),4.92(d,J＝8.0Hz,1H),4.05(d,J＝17.2Hz,1H),3.85(dd,J＝9.8,7.4Hz,1H),3.56-3.65(m,3H),1.23(d,J＝6.4Hz,3H),1.09(d,J＝6.0Hz,12H)ppm;HRMS(ESI positive):calcd for[M+H]+,C27H36ClN4O5:531.2369;found 531.2369.
YMSA-0973
To YMSA-0974 (5.8 mg,0.01 mmol) dissolved in pyridine 0.15mL was added acetic anhydride (150. Mu.L, 1.59 mmol) and dimethylaminopyridine (1.3 mg, 1.1. Mu. Mol), and the mixture was stirred at room temperature for 24 hours. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate=2:1, 1% et 3 N) to give the compound as a colorless solid YMSA-0973(7.0mg,0.011mmol,98％).1H NMR(300MHz,CDCl3/TMS):δ＝8.78(s,1H),8.02(d,J＝2.7Hz,1H),7.92-7.95(m,2H),7.80-7.85(m,1H),7.73(m,1H),7.56-7.62(m,1H),7.48(brs,1H),5.51(dd,J＝10.5,7.8Hz,1H),5.25(d,J＝2.7Hz,1H),5.11-5.16(m,2H),4.02(d,J＝18.3Hz,1H),3.68-3.76(m,2H),2.22(s,3H),2.16(s,3H),2.03(s,3H),1.16(d,J＝6.3Hz,3H),1.05(d,J＝6.3Hz,6H),1.03(d,J＝6.0Hz,6H)ppm;HRMS(ESI positive):calcd for[M+H]+,C33H42 35ClN4O8:657.2686;found 657.2685.
EXAMPLE 39 Synthesis of YMSA-1012
[ Chemical formula 39]
2- ((Trans-3, 5-dimethylpiperidin-1-yl) methyl) -4-nitrophenol (25)
To a solution of 3, 5-lutidine 23 (2.3 mL,20 mmol) in tetrahydrofuran 20mL was added super hydrate TM (1M solution, 60mL,60 mmol) in THF and stirred at room temperature for 14 hours. After completion of the reaction, methanol was added until no foaming occurred. The resulting mixture was diluted with diethyl ether and extracted with 1N hydrochloric acid. After the aqueous layer was neutralized with a 3N aqueous sodium hydroxide solution, extraction was performed with ethyl acetate. The organic phase was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine, then dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 2.72g of a 24-phase mixture. 1.35g of the resulting mixture was dissolved in 10mL of tetrahydrofuran, and triethylamine (2.8 mL,20 mmol) and 2-hydroxy-5-nitrobenzyl bromide (1.15 g,5 mmol) were added thereto and stirred under reflux for 11 hours. After completion of the reaction was confirmed, the solvent was distilled off, and the residue was diluted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was diluted with diethyl ether, dioxane hydrochloride solution was added until precipitation was produced, and cooled with ice. The obtained precipitate was washed with diethyl ether, and then the solvent was distilled off under reduced pressure. The resulting white solid was dissolved in water and purified by HPLC (mobile phase: 0.1% aqueous tfa/0.1% acetonitrile tfa=85/15). After lyophilization, 25 (34.2 mg, 1%) as a white solid was obtained as the cis-form (29.5mg,1％).1H NMR(300MHz,CDCl3/TMS):8.09(dd,J＝3.0,9.0Hz,1H),7.92(d,J＝3.0Hz,1H),6.83(d,J＝9.0Hz,1H),3.77(s,2H),2.90(d,J＝8.4Hz,2H),1.81-1.66(m,5H),0.99(brs,1H),0.89(d,J＝5.7Hz,6H)ppm.
2-Chloro-6- ((trans-3, 5-dimethylpiperidin-1-yl) methyl) -4-nitrophenol (26)
To a solution of compound 25 (34.2 mg,0.13 mmol) dissolved in acetonitrile 1.8mL and acetic acid 0.2mL was added N-chlorosuccinimide (20.8 mg,0.16 mmol), and the mixture was stirred at room temperature for 5.5 hours. The solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and the compound was isolated as a yellow solid 26(21.3mg,55％).1H NMR(300MHz,CDCl3/TMS):δ＝8.23(d,J＝2.7Hz,1H),7.83(d,J＝2.7Hz,1H),3.88(d,J＝14.4Hz,1H),3.69(d,J＝14.4Hz,1H),2.10-2.04(m,5H),1.03(br,9H)ppm.
YMSA-1012
To a solution of compound 26 (21.3 mg,0.07 mmol) dissolved in 2mL of ethanol was added tin chloride dihydrate (64 mg,0.29 mmol) and stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (23 mg,0.14 mmol) was added to the reaction solution, and the mixture was stirred again under reflux for 1.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 2N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to isolate the compound as a pale yellow solid YMSA-1012(26.1mg,93％).M.p.89-90℃.IR(ATR):ν＝2924,2162,1620,1572,1533,1499,1468,1394,1357,1235,1122,1067,1027,995,960,917,868,820,765,727,679,590,557,537,498,466,433,416cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.74(s,1H),7.93-7.90(m,1H),7.84-7.81(m,2H),7.60-7.56(m,2H),7.30-7.23(m,2H),3.80(d,J＝13.8Hz,1H),3.57(d,J＝3.57,1H),2.05(br,4H),1.37-1.26(m,4H),1.00(brs,6H)ppm.13CNMR(100MHz,CDCl3/TMS):δ＝166.8,157.7,154.6,150.1,149.5,133.0,130.5,127.8,126.2,123.0,122.9,122.8,122.0,118.5,60.8,59.3,48.6,37.8,27.2,18.7ppm.HRMS(ESI+):calcd for[M+H]+,C22H26ClN4O:397.1795;found 397.1790.
EXAMPLE 40 Synthesis of YMSA-1015
[ Chemical formula 40]
3- (2-Hydroxy-5-nitrobenzyl) -3-azabicyclo [3.2.1] octane-8-ol (28)
To a solution of 2-hydroxy-5-nitrobenzyl bromide (0.23 g,1.0 mmol) in 4mL of tetrahydrofuran was added 27 (152 mg,1.2 mmol) and triethylamine (0.31 mL,2.2 mmol) and stirred under reflux for 3 hours. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate: methanol=4:1) and the compound was isolated as a yellow solid 28(0.26g,94％).1H NMR(300MHz,CDCl3/TMS):δ＝8.10(dd,J＝8.7,2.7,1H),7.90(s,1H),6.82(d,J＝9.3Hz,1H),4.16-4.09(m,1H),3.77(s,2H),3.31(s,2H),2.30-2.26(m,2H),2.18-2.06(m,4H),1.88-1.83(m,2H).
3- (3-Chloro-2-hydroxy-5-nitrobenzyl) -3-azabicyclo [3.2.1] octane-8-ol (29)
To a solution of compound 28 (260 mg,0.94 mmol) dissolved in 9mL of acetonitrile and 1mL of acetic acid was added N-chlorosuccinimide (151 mg,1.1 mmol), and the mixture was stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate: methanol=4:1) and the compound was isolated as a yellow solid 29(102mg,35％).1H NMR(300MHz,DMSO-d6/TMS):δ＝8.05-8.02(m,2H),4.87(s,1H),4.07(s,2H),3.88(s,1H),3.75(s,2H),2.34-2.07(m,6H),1.88-1.84(m,2H).
YMSA-1015(TTn-152)
To a solution of compound 29 (63 mg,0.2 mmol) dissolved in 4mL of ethanol was added tin chloride dihydrate (0.18 g,0.8 mmol) and stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (66 mg,0.4 mmol) was added to the reaction solution, and the mixture was stirred again under reflux for 6 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (ethyl acetate: methanol=4:1) and the compound was isolated as a yellow solid YMSA-1015(95mg,quant.).M.p.60-62℃.IR(ATR):ν＝2926,1620,1575,1531,1473,1395,1357,1317,1224,1125,1072,1044,967,919,867,832,749,681,584,466,431,413cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.74(s,1H),7.93(d,J＝7.8Hz,1H),7.84-7.78(m,3H),7.58-7.53(m,3H),4.10(s,1H),3.77(s,2H),3.33(s,2H),2.26-2.16(m,6H),1.83-1.78(m,2H).13CNMR(100MHz,CDCl3/TMS):δ＝157.7,154.6,151.2,149.5,132.9,129.9,127.7,126.2,123.2,123.1,122.8,122.3,118.7,115.0,79.2,62.1(2C),57.8(2C),55.3(2C),25.3(2C)ppm.HRMS(ESI+):calcd for[M+H]+,C22H24ClN4O2:411.1588;found 411.1584.
EXAMPLE 41 Synthesis of YMSA-1026
[ Chemical formula 41]
YMSA-1026(TTn-152)
To a solution of compound 30 (39.7 mg,0.13 mmol) dissolved in 2mL of ethanol was added tin chloride dihydrate (0.12 g,0.53 mmol) and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (47 mg,0.26 mmol) was added to the reaction solution, and stirred again under reflux for 3 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and the compound was isolated as a yellow solid YMSA-1026(46.1mg,89％).1H NMR(300MHz,CDCl3/TMS):δ＝8.70(s,1H),7.84(dd,J＝5.7,9.0Hz,1H),7.56-7.52(m,2H),7.34-7.21(m,2H),3.87(s,2H),2.62-2.51(m,3H),1.68-1.59(m,3H),1.49-1.39(m,3H),1.15(t,J＝6.9Hz,3H),1.00(t,J＝7.5Hz,6H)ppm.
EXAMPLE 42 Synthesis of YMSA-1062
[ Chemical formula 42]
2- ((Isopropylamino) methyl) -4-nitrophenol (32)
Compound 31 (0.84 g,5.00 mmol) was dissolved in 25mL of methanol, isopropylamine (0.51 mL,5.95 mmol) was added and stirred at room temperature for 1 hour. Sodium borohydride (0.23 g,6.04 mmol) was added to the reaction solution under ice-cooling, and the mixture was stirred for 1 hour. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained mixture was purified by silica gel column chromatography (ethyl acetate: methanol=5:1), whereby the compound was isolated as a yellow solid 32(1.00g,95％).M.p.182.5-184.4℃.IR(ATR):ν＝2948,2718,2662,2545,2491,1590,1623,1590,1564,1477,1443,1432,1375,1255,1168,1149,1123,1089,994,938,919,898,841,821,775,761,733,645,611,558,540,497,477,456,422cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.07(dd,J＝8.9,3.0Hz,1H),7.94(d,J＝3.0,1H),6.84(d,J＝9.0,1H),4.10(s,2H),2.96-2.86(m,1H),1.18(d,J＝6.0,6H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝165.4,140.0,125.3,124.3,122.6,116.9,49.7,48.5,22.3ppm.[M+H]+,C10H15N2O3:211.1077;found 211.1083.
2-Chloro-6- ((isopropylamino) methyl) -4-nitrophenol (33)
To a solution of compound 32 (0.85 g,4.04 mmol) dissolved in 22.8mL of acetonitrile and 2.53mL of acetic acid was added N-chlorosuccinimide (0.59 g,4.46 mmol), and the mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure, and then methanol was added to the resulting mixture. The precipitate formed is filtered off and, after washing with methanol, the positive ion pattern of compound 33(0.26mg,26％).M.p.222.0-224.0℃.IR(ATR):ν＝3148,2975,2295,1586,1563,1480,1456,1435,1391,1348,1298,1280,1209,1167,1131,1089,11077,1018,1004,963,923,906,883,858,849,826,782,760,746,719,657,581,535,472,446cm-1.1H NMR(300MHz,CD3OD/TMS):δ＝8.18(d,J＝3.0Hz 1H),8.06(d,J＝3.0,1H),4.13(s,2H),3.42-3.294(m,1H),1.37(d,J＝6.6,6H)ppm.13C NMR(100MHz,DMSO/TMS):δ＝172.3,128.5,127.2,126.4,123.2,120.4,49.7,45.9,19.2ppm.HRMS(ESI( is isolated as a yellow solid )):calcd for[M+H]+,C10H14 35ClN2O3:245.0687;found 245.0686.
YMSA-1130(TY-3)
To a solution of compound 33 (10 mg,0.04 mmol) dissolved in 3mL of ethanol was added tin chloride dihydrate (46 mg,0.20 mmol) and stirred under reflux for 4 hours. After cooling to room temperature, 4-chloroquinazoline (14 mg,0.08 mmol) was added to the reaction solution, and stirred again under reflux for 2 hours. After completion of the reaction was confirmed, a saturated aqueous sodium hydrogencarbonate solution was added thereto, and extraction was performed with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. Purifying the resulting mixture by silica gel column chromatography (chloroform: methanol=5:1), separating compound YMSA-1130(16mg,quant.).M.p.107.1-110.2℃.IR(ATR):ν＝3184,2975,1621,1601,1576,1530,1498,1465,1393,1367,1321,1287,1252,1230,1154,1136,1125,1078,1014,977,948,926,906,866,850,820,808,756,746,675,592,551,516,485,471,427cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.73(s,1H),7.93-7.78(m,3H),7.58-7.53(m,2H),7.62-7.54(m,2H),7.35(d,J＝2.4Hz 1H),4.06(s,2H),2.99-2.93(m,1H),2.01(s br,1H),1.21(d,6H)ppm.13C NMR(100MHz,CHCl3/TMS):δ＝158.0,155.0,152.1,149.9,133.1,129.2,128.8,126.7,124.1,123.9,121.9,121.2,115.0,50.0,48.6,22.3ppm.HRMS(ESI( positive ion mode as yellow solid)) calcd for [ m+h ] +,C18H20 35ClN4 O343.1320; found 343.1420.
YMSA-1062(TY-4)
To YMSA-1130 (0.510 g,0.15 mmol) dissolved in 1mL of dimethylformamide were added carbonyldiimidazole (0.25 g,0.15 mmol) and triethylamine (25.3. Mu.L, 0.18 mmol), and the mixture was stirred at 80℃for 20 hours. After completion of the reaction was confirmed, water was added thereto, and extraction was performed with diethyl ether. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (chloroform: methanol=10:1) to isolate compound YMSA-1062(12.4mg,23％).M.p.261.2-269.1℃.IR(ATR):ν＝3388,3119,2968,1698,1625,1609,1569,1533,1489,1470,1438,1416,1394,1372,1353,1328,1310,1280,1251,1227,1210,1192,1141,1132,1073,1047,990,968,917,896,874,864,820,792,765,737,705,677,662,615,596,583,539,511,502,482,468,438,403cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝8.80(s,1H),7.98-7.95(m,1H),7.88-7.80(m,2H),7.64-7.56(m,2H),7.36(s,1H),4.73-4.68(m,1H),4.42(s,2H),1.30(d,J＝6.7Hz 6H)ppm.13C NMR(100MHz,CHCl3/TMS):δ＝157.7,154.9,150.3,150.0,142.6,135.0,133.5,129.4,127.3,123.0,121.6,120.6,119.9,117.9,115.3,48.4,41.4,19.3ppm.HRMS(ESI( as a yellow solid in positive ion mode )):calcd for[M+H]+,C19H18 35ClN4O2:369.1113;found 369.1109.
EXAMPLE 43 Synthesis of YMSA-1055
[ Chemical formula 43]
N-ethyl-N- (3-nitrobenzyl) propan-2-amine (35)
To a solution of 3-nitrobenzyl bromide (216 mg,1.0 mmol) in 2mL of tetrahydrofuran was added compound 34 (145. Mu.L, 1.2 mmol) and triethylamine (306. Mu.L, 2.2 mmol), and the mixture was stirred under reflux for 1 hour. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1), and compound 35 (120 mg, 54%) was isolated as a pale yellow oil.
YMSA-1055
To a solution of compound 35 (120 mg,0.54 mmol) in 5mL of ethanol was added tin chloride dihydrate (0.49 g,2.15 mmol) and stirred under reflux for 2 hours. After cooling to room temperature, 4-chloroquinazoline (178 mg,1.1 mmol) was added to the reaction solution, and stirred again under reflux for 2 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and the compound was isolated as a yellow solid YMSA-1055(135mg,78％).1H NMR(300MHz,CDCl3/TMS):δ＝8.78(s,1H),7.91(t,J＝9.6Hz,2H),7.84-7.76(m,2H),7.61-7.55(m,2H),7.44(s,1H),7.36(t,J＝7.5Hz,1H),7.16(d,J＝8.1Hz,1H),3.60(s,1H),3.03(sept,J＝6.6Hz,1H),2.51(q,J＝6.6Hz,2H),1.06-1.00(m,9H).13CNMR(100MHz,CDCl3/TMS):δ＝158.0,154.7,149.9,142.1,139.1,133.1,128.2,128.0,126.4,123.8,123.2,122.3,121.0,115.4,53.1,49.2,43.3,18.1,14.2ppm.
EXAMPLE 44 Synthesis of YMSA-1066
[ Chemical formula 44]
(±) -2, 5-Dimethylpiperazine-1-carboxylic acid tert-butyl ester (37)
To a chloroform solution (250 mL) of compound 36 (0.50 g,4.5 mmol) was added dropwise a solution of (Boc) 2 O (0.53 g,2.4 mmol) in chloroform (200 mL) under ice-cooling, and the mixture was stirred for 23 hours. After confirming the completion of the reaction, water was added, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. Purifying the resulting mixture by silica gel column chromatography (chloroform: methanol=25:1 to 3:1), separating compound 37(0.32g,62％).IR(ATR):ν＝3333,2972,2932,1679,1456,1414,1364,1339,1317,1247,1149,1119,1099,1059,1037,936,866,815,752,665,592,522,455,408cm-1.1H NMR(300MHz,CDCl3/TMS):δ＝4.16-4.06(m,1H),3.55(dd,J＝15,2.4Hz,1H),3.24-3.08(m,3H),2.48(dd,J＝13,3,1H),1.46(s,9H),1.21(d,J＝6.6,3H),1.17(d,J＝6.9,3H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝155.4,79.3,47.2,46.8,44.0,43.5,28.4,17.1,15.3ppm.HRMS(ESI( positive ion mode as yellow solid)) calcd for [ m+h ] +,C11H23N2O2: 215.1753; found 215.1754.
(±) -2,4, 5-Trimethylpiperazine-1-carboxylic acid tert-butyl ester (38)
Compound 37 (0.20 g,0.93 mmol) was dissolved in 15.5mL of acetone, methyl iodide (0.11 mL,1.8 mmol) and potassium carbonate (0.14 mg,1.0 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed, a saturated aqueous sodium hydrogencarbonate solution was added thereto, and extraction was performed with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=4:1), compound 38(0.15g,73％).1H NMR(300MHz,CDCl3/TMS):δ＝4.22-4.18(m,1H),8.10-8.04(m,1H),3.63(dd,J＝13,1.2,1H),3.23(dd,J＝13,3.6,1H),2.83-2.79(m,1H),2.71-2.63(m,1H),2.27(s,3H),2.22-2.18(m,1H),1.46(s,9H),1.25(d,J＝6.9,3H),0.93(d,J＝6.6,3H)ppm.13C NMR(100MHz,CDCl3/TMS):δ＝155.4,79.2,53.4,52.1,46.8,44.4,42.8,28.4,16.4,7.38ppm.HRMS(ESI( positive ion mode was isolated as a yellow oil)) calcd for [ m+h ] +,C12H25N2O2: 229.1911; found 229.1911.
(±) -1,2, 5-Trimethylpiperazine (39)
Compound 38 (0.12 g,0.52 mmol) was dissolved in 6mL of dichloromethane, trifluoroacetic acid (6 mL) was added, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, the solvent was distilled off, and the compound 39(0.28g,quant.).1H NMR(300MHz,CD3OD/TMS):δ＝3.79-3.66(m,3H),3.54-3.44(m,1H),3.28-3.11(m,1H),2.97(s,3H),1.45(d,6.3,1H),1.40(d,6.3,3H)ppm.HRMS(ESI( positive ion mode) was isolated as a colorless solid, calcd for [ M+H ] +,C7H17N2: 129.1386; found 129.1386.
4-Nitro-2- ((±) -2,4, 5-trimethylpiperazin-1-yl) methyl) phenol (40)
To a solution of 2-hydroxy-5-nitrobenzyl bromide (0.13 g,0.56 mmol) in 1mL of tetrahydrofuran was added 39 (0.20 g,0.84 mmol) and triethylamine (240. Mu.L, 1.68 mmol), and the mixture was stirred under reflux for 1 hour. After completion of the reaction was confirmed, the solvent was distilled off under reduced pressure, and then a saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. Purifying the resulting mixture by silica gel column chromatography (ethyl acetate), and separating compound 40(81.6mg,52％).1H NMR(300MHz,CDCl3/TMS):δ＝8.09(dd,J＝9.0,2.7Hz,1H),7.93(d,J＝2.7,1H),6.83(d,J＝8.7,1H),4.43(d,J＝15,1H),3.33(d,J＝14,1H),2.83(dd,J＝12,2.7,1H),2.74(dd,J＝11,1.8,1H)2.65-2.61(m,1H),2.28(s,3H),2.15-2.03(m,3H),1.21(d,J＝6.3,3H),1.01(d,J＝6.0,3H)ppm.HRMS(ESI( positive ion pattern as yellow solid)) calcd for [ M+H ] +,C14H22N3O3: 280.1656; found280.1659.
2-Chloro-4-nitro-6- ((+ -) -2,4, 5-trimethylpiperazin-1-yl) methyl) phenol (41)
To a solution of compound 40 (59 mg,0.21 mmol) dissolved in 2.07mL of acetonitrile and 0.23mL of acetic acid was added N-chlorosuccinimide (62 mg,0.46 mmol), and the mixture was stirred at room temperature for 6 days. The solvent was distilled off under reduced pressure, and then 10% aqueous sodium thiosulfate solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine, then dried over sodium sulfate, the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=10:1 to 4:1) and compound 41(14.8mg,22％).1H NMR(300MHz,CDCl3/TMS):δ＝8.22(d,J＝2.7Hz 1H),7.85(d,J＝2.4,1H),4.46(d,J＝15,1H),3.42(d,J＝14,1H),2.86(dd,J＝12,3.3,1H),2.80-2.73(m,2H),2.29(s,3H),2.24-2.07(m,3H),1.24(d,J＝6.3,3H),1.04(d,J＝6.0,3H)ppm.HRMS(ESI( was isolated as a yellow solid in positive ion mode )):calcd for[M+H]+,C14H21 35ClN3O3:314.1266;found 314.1267.
YMSA-1066(TY-2)
To a solution of compound 41 (12 mg,0.04 mmol) dissolved in 2mL of ethanol was added tin chloride dihydrate (27 mg,0.12 mmol) and stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (7.4 mg,0.05 mmol) was added to the reaction solution, and stirred again under reflux for 3 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then 1N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. Purifying the resulting mixture by silica gel column chromatography (ethyl acetate: methanol=10:1 to 5:1), separating compound YMSA-1066(4.7mg,29％).1H NMR(300MHz,CDCl3/TMS):δ＝8.75(s,1H),7.93(d,J＝2.1Hz,1H),7.84-7.79(m,2H),7.62-7.54(m,2H),7.31(d,J＝2.7,1H),4.47(d,J＝14,1H),3.26(d,J＝14,1H),2.87-2.83(m,2H),2.64(s br,1H),2.28-2.04(m,6H),1.23(d,J＝6.0,3H),1.03(d,J＝6.3,3H)ppm.HRMS(ESI( as a yellow solid in positive ion mode) calcd for [ m+h ] +,C22H27 35ClN5 O412.1899; found 412.1900.
EXAMPLE 45 Synthesis of YMSA-1111
[ Chemical formula 45]
YMSA-1111
To a solution of compound 42 (11.5 mg,0.035 mmol) dissolved in 1mL of ethanol was added tin chloride dihydrate (31 mg,0.14 mmol) and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (12 mg,0.07 mmol) was added to the reaction solution, and the mixture was stirred again under reflux for 1.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to isolate the compound as a pale yellow solid YMSA-1111(15.4mg,quant).1H NMR(300MHz,DMSO-d6/TMS):δ＝9.60(s,1H),8.50(s,1H),8.46(d,J＝7.8Hz,1H),7.84-7.79(m,1H),7.74-7.72(m,2H),7.61-7.56(m,1H),7.40(d,J＝2.4Hz,1H),5.52(s,2H),3.67(s,2H),3.01(sept,J＝6.6Hz,2H),1.03(d,J＝6.6Hz,12H),13CNMR(100MHz,CDCl3/TMS):δ＝157.9,155.2,149.9,141.5,132.8,128.9,127.6,126.4,125.2,124.0,122.9,120.3,119.2,115.0,49.2,47.1,20.1ppm.HRMS(FAB+):calcd for[M+H]+,C21H27ClN5:384.1955;found 384.1949.
EXAMPLE 46 Synthesis of YMSA-1112
[ Chemical formula 46]
N- (2- (difluoromethoxy) -5-nitrobenzyl) -N-ethyl-N-propan-2-amine (44)
To a solution of compound 43 (457 mg,1.89 mmol) dissolved in 10mL of 50% acetonitrile in water at-78deg.C was added potassium hydroxide (2.1 g,3.79 mmol) and BrCF2PO(OEt)2(11H NMR(300MHz,CDCl3/TMS):δ＝8.57(d,J＝3.0Hz,1H),8.10(dd,J＝3.0,9.0Hz,1H),6.66(t,J＝72.6Hz,1H),3.64(s,2H),2.99(sept,J＝6.6Hz,1H),2.53(q,J＝6.9Hz,2H),1.06-0.98(m,9H)ppm.
YMSA-1117
To a solution of compound 44 (58 mg,0.2 mmol) dissolved in 3mL of ethanol was added tin chloride dihydrate (181 mg,0.8 mmol) and stirred under reflux for 1 hour. After cooling to room temperature, 4-chloroquinazoline (66 mg,0.4 mmol) was added to the reaction solution, and stirred again under reflux for 2.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to isolate the compound as a colorless solid YMSA-1117(31mg,41％).1H NMR(300MHz,CDCl3/TMS):δ＝8.76(s,1H),7.92(t,J＝8.4Hz,1H),7.89-7.76(m,3H),7.62-7.57(m,1H),7.15(d,J＝8.7Hz,1H),6.58(t,J＝74.7Hz,1H),3.64(s,2H),3.02(sept,J＝6.6Hz,1H),2.54(q,J＝7.5Hz,2H),1.07-1.01(m,9H)ppm.13CNMR(100MHz,CDCl3/TMS):δ＝154.9,132.9,129.1,126.7,123.9,121.3,120.5,120.3,50.0,47.5,44.0,18.1,13.9ppm.HRMS(ESI+):calcd for[M+H]+,C21H25F2N4O:387.1996;found 387.1984.
N- (3-chloro-2- (difluoromethoxy) -5-nitrobenzyl) -N-ethyl-N-propan-2-amine (46)
To a solution of compound 45 (273 mg,1 mmol) dissolved in 10mL of 50% acetonitrile in water at-78deg.C were added potassium hydroxide (1.1 g,20 mmol) and BrCF2PO (OEt) 2 (356. Mu.L, 2 mmol), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction was confirmed, H 2 O was added to the reaction mixture, and extraction was performed with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (hexane: ethyl acetate=10:1) to isolate the compound as a colorless oil 46(129mg,40％).1H NMR(300MHz,CDCl3/TMS):δ＝8.54(d,J＝2.7Hz,1H),8.19(d,J＝2.7Hz,1H),6.70(t,J＝74.1Hz,1H),3.71(s,2H),2.97(sept,J＝6.6Hz,1H),2.52(q,J＝6.9Hz,2H),1.05-0.98(m,9H)ppm.
YMSA-1112
To a solution of compound 46 (129 mg,0.40 mmol) dissolved in 6mL of ethanol was added tin chloride dihydrate (362 mg,1.6 mmol) and stirred under reflux for 1.5 hours. After cooling to room temperature, 4-chloroquinazoline (132 mg,0.8 mmol) was added to the reaction solution, and the mixture was stirred again under reflux for 1.5 hours. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure, and then a 3N aqueous sodium hydroxide solution was added thereto, followed by extraction with ethyl acetate. After the organic phase was washed with saturated brine, it was dried over sodium sulfate, and the solid was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to isolate the compound as a pale yellow solid YMSA-1112(150mg,89％).IR(ATR):ν＝3112,2970,1626,1609,1574,1535,1503,1462,1418,1381,1354,1322,1207,1179,1102,1050,927,915,880,865,841,819,794,761,720,676,635,609,573,531,509,486,458,433,406ppm.1H NMR(300MHz,CDCl3/TMS):δ＝8.81(s,1H),8.19(d,J＝2.7Hz,1H),7.98-7.82(m,3H),7.70(d,J＝2.4Hz,1H),7.64-7.58(m,1H),7.47(s,1H),6.64(t,J＝75.3Hz,1H),3.70(s,2H),3.00(sept,J＝6.6Hz,1H),2.54(q,J＝6.9Hz,2H),1.07-1.01(m,9H)ppm.13CNMR(100MHz,CDCl3/TMS):δ＝157.6,154.2,149.7,140.2,138.0,137.3,133.2,127.9,126.4,126.0,123.1,122.1,121.4,117.9,115.1,49.8,47.3,43.8,17.9(2C),13.9(2C)ppm.HRMS(ESI+):calcd for[M+H]+,C21H24ClF2N4O:421.1607;found421.1600.
EXAMPLE 47 Synthesis of YMSA-1033
[ Chemical formula 47]
YMSA-1033 was obtained in the same manner as in example 21.
All publications, patents, and patent applications cited in this specification are incorporated herein by reference.

Claims (5)

1.下述式(I)表示的化合物、其盐、它们的溶剂合物、或它们的前药，1. A compound represented by the following formula (I), a salt thereof, a solvate thereof, or a prodrug thereof, [化学式1][Chemical formula 1] 式(I)中，R1、R2及R3相同或不同，为氢原子、卤素原子、取代或未取代的C1-6-烷基、取代或未取代的C1-6-烷氧基、或者-N(Ra)(Rb)，其中，Ra及Rb相同或不同，为取代或未取代的C1-10-烷基、或者取代或未取代的芳基，Ra及Rb可以与相邻的氮原子一起形成取代或未取代的5～7元环，In formula (I), R 1 , R 2 and R 3 are the same or different and are hydrogen atoms, halogen atoms, substituted or unsubstituted C 1-6 -alkyl groups, substituted or unsubstituted C 1-6 -alkoxy groups, or -N(R a )(R b ), wherein R a and R b are the same or different and are substituted or unsubstituted C 1-10 -alkyl groups, or substituted or unsubstituted aryl groups, and R a and R b may form a substituted or unsubstituted 5- to 7-membered ring together with the adjacent nitrogen atom, R4为-N(Ra)(Rb)，其中，Ra及Rb相同或不同，为取代或未取代的C1-10-烷基、或者取代或未取代的芳基，Ra及Rb可以与相邻的氮原子一起形成取代或未取代的5～7元环， R4 is -N(R a )(R b ), wherein R a and R b are the same or different and are substituted or unsubstituted C 1-10 -alkyl, or substituted or unsubstituted aryl, and R a and R b may form a substituted or unsubstituted 5- to 7-membered ring together with the adjacent nitrogen atom, X为氢原子、氟原子、氯原子、溴原子或碘原子，X is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, 式中的羟基可以被保护基取代。The hydroxy group in the formula may be substituted by a protecting group. 2.如权利要求1所述的化合物、其盐、它们的溶剂合物、或它们的前药，其中，所述式(I)中，R4为乙基(异丙基)氨基、二异丙基氨基、环己基(乙基)氨基、乙基(戊烷-3-基)氨基、叔丁基(乙基)氨基或3,5-二甲基哌啶子基。2. The compound, salt thereof, solvate thereof, or prodrug thereof according to claim 1, wherein in the formula (I), R 4 is ethyl(isopropyl)amino, diisopropylamino, cyclohexyl(ethyl)amino, ethyl(pentan-3-yl)amino, tert-butyl(ethyl)amino or 3,5-dimethylpiperidino. 3.如权利要求1或2所述的化合物、其盐、它们的溶剂合物、或它们的前药，其中，所述式(I)中，R1、R2及R3相同或不同，为氢原子、卤素原子、C1-6-烷氧基或二甲基氨基。3. The compound, salt thereof, solvate thereof, or prodrug thereof according to claim 1 or 2, wherein in the formula (I), R1 , R2 , and R3 are the same or different and are hydrogen atom, halogen atom, C1-6 -alkoxy group or dimethylamino group. 4.如权利要求1～3中任一项所述的化合物、其盐、它们的溶剂合物、或它们的前药，其中，所述式(I)中，X为氢原子或氯原子。4 . The compound, salt thereof, solvate thereof, or prodrug thereof according to claim 1 , wherein in the formula (I), X is a hydrogen atom or a chlorine atom. 5.抗SARS-CoV-2药，其含有权利要求1～4中任一项所述的化合物、其盐、它们的溶剂合物、或它们的前药。5. An anti-SARS-CoV-2 drug comprising the compound according to any one of claims 1 to 4, a salt thereof, a solvate thereof, or a prodrug thereof.
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